Diseases of Bone and Joints (Non-neoplastic and Non-infectious Disorders of Bone, Skeletal Dysplasias/Dysostoses, Constitutional Bone Disorders)

Clinical Features

The chief clinical characteristic of osteogenesis imperfecta is the extreme fragility and porosity of the bones, with an attendant proneness to fracture. The fractures heal readily, but the new bone is of a similar imperfect quality.

The age of onset of symptoms varies depending on the type of OI with fractures in type I and IV occurring during infancy and type II in utero. In type III, half the cases present fracture in utero, and other half in the neonatal period. No known differences based on gender exist. Prenatal screening by ultrasound during the second trimester shows bowing of long bones, fractures, limb shortening, and decreased skull echogenicity.

A second characteristic clinical feature of osteogenesis imperfecta is the occurrence of pale blue sclerae. The sclerae are abnormally thin, and for this reason the pigmented choroid shows through and produces the bluish color. However, the appearance of blue sclera is not confined to this disease since it may also be seen in osteopetrosis, fetal rickets, Turner syndrome, Paget’s disease, Marfan syndrome, and EhlersDanlos syndrome, as well as in normal infants. While the blue sclerae are a prominent sign in this disease, they are not invariably present. In a series of 42 patients reported by Bauze and his associates, 12 of the patients had white sclerae, and these were generally found in the older patients with the more severe disease and earlier onset of fractures.

In a thorough review of osteogenesis imperfecta and dentinogenesis imperfecta by Winter and Maiocco, the following additional signs and symptoms were described as being characteristic of osteogenesis imperfecta: deafness due to otosclerosis, abnormalities of the teeth (identical to those of dentinogenesis imperfecta, or ‘hereditary opalescent dentin’), laxity of the ligaments, a peculiar shape of the skull and an abnormal electrical reaction of the muscles.

Many patients with osteogenesis imperfecta also have a tendency towards capillary bleeding although no specific blood dyscrasia or defect has been demonstrated.

Physical features can vary depending on the type. It forms the basis for Sillence classification.

Oral Manifestations

Osteogenesis imperfecta is basically a disturbance of mesodermal tissues, particularly the calcified tissues. When a widespread congenital disturbance in bone formation exists, it is only logical to expect a concomitant disturbance in dentin formation. The large head size, frontal and temporal bossing, and exaggerated occiput create a greater percentage of class III malocclusions. Anterior and posterior cross bites and open bites are also frequent. These conditions seem to be caused by maxillary hypoplasia rather than mandibular hyperplasia. A surprising large number of impactions and ectopic teeth have been reported. In permanent dentition, OI patients often have unerupted first and second molars, a condition which is rare in the general population. These abnormalities have no relation to the existence of dentinogenesis imperfecta. Dentinogenesis imperfecta represents the disturbance in tooth formation associated with OI, and is one of the most significant clinical patterns of OI. It can be the only abnormality noted at times amongst the spectra of clinical manifestations. Therefore, clinical and radiological evaluations of the dentition may be the only affirmative component in the diagnosis of a questionable case of OI.

Radiographic Features

The radiographic hallmarks of osteogenesis imperfecta include osteopenia, bowing, angulation or deformity of the long bones, multiple fractures, and wormian bones (sutural bone) in the skull.

Histologic Findings

The bones in patients with osteogenesis imperfecta exhibit thin cortices, sometimes being composed of immature spongy bone, while the trabeculae of the cancellous bone are delicate and often show microfractures (Fig. 17-1). Osteoblastic activity appears retarded and imperfect, and for this reason the thickness of the long bones is deficient. The basic defect appears to lie in the organic matrix with failure of fetal collagen to be transformed into mature collagen. Qualitative defects (abnormal collagen I molecule) and quantitative defects (decrease in production of normal collagen I molecules) both exist. There is some evidence that the progressive intermolecular cross-linkage of adjacent collagen molecules, which is an essential characteristic of normal collagen maturation, is defective in this disease. Calcification proceeds normally. Defective microvascular system and decreased collagen fibril diameter have also been observed. The length of the long bones is usually normal unless multiple fractures have caused undue shortening.

Treatment and Prognosis

There is no known treatment for osteogenesis imperfecta. No medical therapy is involved, other than the treatment of infections when they occur. The prognosis varies from relatively good to very poor. In type IA, life expectancy is similar to that of general population; type II, most patients die within the first year of life. A slight decrease in life expectancy has been observed in the other types.

Clinical Features

The estimated incidence of Marfan syndrome ranges from 1 in 5,000 to 1 in 10,000 births which includes stillbirths. The wide variation in the sites of mutations noticed in the fibrillin gene causes the varied phenotypic manifestations of this syndrome. Several other diseases present similar to Marfan syndrome, making it exceedingly difficult to determine the exact incidence. The skeleton typically displays multiple deformities including arachnodactyly, dolichostenomelia (i.e. long limbs relative to trunk length), and thoracolumbar scoliosis. The shape of the skull and face is characteristically long and narrow, and commonly suggests the diagnosis of the disease (Figs. 17-2, 17-3). Other features of the disease include hyperextensibility of joints with habitual dislocations, kyphosis and flat feet. In the cardiovascular system, aortic dilation, aortic regurgitation, and aneurysms are the most worrisome clinical findings. Mitral valve prolapse requiring valve replacement can occur as well. Ocular findings include myopia, cataracts, retinal detachment, and superior dislocation of the lens.

Oral Manifestations

According to Baden and Spirgi, who have reviewed the oral manifestations of this disease, a high, arched palatal vault is very prevalent and may be a constant finding. Bifid uvula is also reported as well as malocclusion. In addition, multiple odontogenic cysts of the maxilla and mandible have occasionally been reported, most recently by Oatis and his coworkers. One additional finding sometimes present, is temporomandibular dysarthrosis (Fig. 17-4).

Radiographic Features

Skull radiographs (AP and lateral) may demonstrate a high arched palate, increased skull height, and an enlarged frontal sinus.

Treatment and Prognosis

There is no specific treatment for this condition. Recent strides in the management of the cardiovascular manifestations of Marfan syndrome have led to a significant decrease in morbidity and mortality. Patient longevity now approaches that of persons without Marfan syndrome, although cardiovascular compromise is still the most common cause of patient death.

Etiology

Type IA is an autosomal recessive disorder with an unknown chromosomal locus. Type IB is an autosomal recessive disorder resulting from mutations of the DDST (diastrophic dysplasia sulfate transporter) gene, which is located at 5q32– q33. Type II is an autosomal dominant type collagenopathy resulting from mutations in the COL2A1 (collagen 2 αl chain) gene, which is located at 12q13.1–q13.3. Different mutations in the gene encoding type II collagen (COL2A1) cause achondrogenesis type II as well as other type II collagenopathies (e.g. spondyloepiphyseal dysplasias, hypochondrogenesis).

Clinical Features

Achondrogenesis type I results in still-birth more frequently than type II. Males and females are affected equally. Achondrogenesis is detected prenatally or at birth because of typical clinical, radiographic, histological, and molecular findings.

In achondrogenesis type I, the craniofacial features include a disproportionately large head, soft skull, sloping forehead, convex facial plane, flat nasal bridge, occasionally associated with a deep horizontal groove, small nose, often with anteverted nostrils, long philtrum, retrognathia, increased distance between lower lip and lower edge of chin and double chin appearance (often). In achondrogenesis type II, the features seen are a disproportionately large head, large and prominent forehead, flat facial plane, flat nasal bridge, small nose with severely anteverted nostrils, normal philtrum (often), micrognathia (Fig. 17-5). The differential diagnoses include achondroplasia, hypophosphatasia, osteogenesis imperfecta and thanatophoric dysplasia.

Radiographic Features

The radiographic features may vary, and no single feature is consistently noticed. Distinction between type IA and type IB on radiographs is not always possible. Degree of ossification is age dependent, and caution is needed when comparing radiographs at different gestational ages.

Treatment and Prognosis

Medical care is supportive. No treatment is available for the underlying disorder. The condition is universally lethal.

Etiology

Patients with hypophosphatasia have defects in mineralization of bone due to TNSALP (tissue nonspecific alkaline phosphatase) deficiency. A mutation in the gene coding for tissue nonspecific alkaline phosphatase is believed to be the cause of hypophosphatasia. The gene, designated ALPL, is located at band 1p36.1–34.

Clinical Features

Hypophosphatasia affects all age groups; however, the severity of the disease differs with age. Males and females are affected equally. Hypophosphatasia occurs in all races. The perinatal form is considered lethal, while the infantile form has a mortality rate of 50%. Individuals with the other forms can reach adulthood, although often with increased morbidity. Patients with the childhood form often have rachitic deformities, and those with the adult type have increased morbidity from poorly healing stress fractures. All patients are affected by premature loss of dentition.

The perinatal form has the most severe manifestations. It is usually diagnosed at birth, and the infant rarely survives for more than a few hours. Death is due to respiratory failure. Marked hypocalcification of the skeletal structures is observed.

Patients with the infantile form may appear normal at birth; however, the clinical signs of hypophosphatasia appear during the first six months. This form also has respiratory complications due to rachitic deformities of the chest. Despite the presence of an open fontanelle, premature craniosynostosis is a common finding that may result in increased intracranial pressure. Hypercalcemia is also present and increased excretion of calcium may lead to renal damage.

Skeletal deformities, such as dolichocephalic skull and enlarged joints, a delay in walking, short stature, and a waddling gait accompany the childhood form. A history of fractures and bone pain usually exists as well. Premature loss of dentition is common with the incisor teeth often being the first affected.

The adult form presents during middle age. The first complaint may be foot pain, which is due to stress fractures of the metatarsals. Thigh pain, due to pseudofractures of the femur, may also be a presenting symptom. Upon obtaining an in-depth history, many of these patients will reveal that they had premature loss of deciduous teeth.

The only physical finding in the odontohypophosphatasic form is the premature loss of teeth.

Oral Manifestations

The earliest manifestation of the disease may be loosening and premature loss of deciduous teeth, chiefly the incisors. There are varying reports of gingivitis; however it does not seem to be a consistent feature of the disease. The differential diagnoses include achondrogenesis, osteogenesis imperfecta, rickets and thanatophoric dysplasia.

Radiographic Features

The childhood form is characterized by rachitic deformities. Upon radiologic examination of the metaphysis, evidence of radiolucent projections from the epiphyseal plate into the metaphysis is present. This is not found in other types of rickets. Radiographic findings are normal for patients with odontohypophosphatasia. Dental radiographs generally reveal hypocalcification of teeth and the presence of large pulp chambers, as well as alveolar bone loss; however these findings have not been consistently reported.

Histologic Findings

Histologic examination of the skeleton will reveal rachitic abnormalities of the growth plates such as failure of cartilage calcification. Both osteoclasts and osteoblasts appear morphologically normal, but the latter lack membrane associated alkaline phosphatase (ALP) activity on histochemical testing. This disrupts incorporation of calcium into the matrix. The long bones characteristically exhibit an increased width of proliferating cartilage with widening of the hypertrophic cell zone, irregularity of cell columns, irregular penetration of the cartilage by marrow with persistence of numerous cartilage islands in the marrow, and formation of large amounts of osteoid which is inadequately calcified. These findings are indistinguishable from those in true rickets. Histological examination of the teeth reveals a decrease in cementum, which varies with the severity of the disease. This is presumably as a result of failure of cementogenesis, so that there is no sound functional attachment of the tooth to bone by periodontal ligament. This lack of attachment is thought to account for the early spontaneous exfoliation of the deciduous teeth. The pulp chamber also appears to be enlarged. The incisors tend to be the most affected. Bone biopsy findings are normal for patients with odontohypophosphatasia.

Treatment and Prognosis

Currently, no medical therapy is available. Various treatments have been attempted including zinc, magnesium, cortisone, plasma, and enzyme replacement therapy. The results have been inconsistent. Orthopedic surgical involvement may be necessary in patients with hypophosphatasia. The perinatal form is considered lethal. The infantile form is thought to be fatal in approximately 50% of patients. Longevity studies have not been conducted for the infantile and childhood forms. Individuals with the adult and odontohypophosphatasia forms are believed to have normal lifespans.

Etiology

The primary underlying defect in all types of osteopetrosis is failure of the osteoclasts to resorb bone. This results in thickened sclerotic bones, which have poor mechanical properties. Increased bone fragility results from a failure of the collagen fibers to augment bone matrix and from defective remodeling of woven bone to compact bone. Heterogeneous molecular or genetic defects can result in impaired osteoclastic function. The exact molecular defects or sites of these mutations largely are unknown.

Clinical Features

Three distinct forms of the disease are based on age and clinical features. These are adult onset, infantile, and intermediate. Other rare forms have been described (e.g. lethal, transient, postinfectious). The infantile and intermediate types have an autosomal recessive mode of transmission, while the adult onset type shows autosomal dominant inheritance. If untreated, infantile osteopetrosis usually results in death by the first decade of life due to severe anemia, bleeding, or infection. Adult patients with osteopetrosis are usually asymptomatic and have good longterm survival rates.

Infantile osteopetrosis (also called malignant osteopetrosis) is diagnosed early in life. Failure to survive and growth retardation are symptoms. Bony defects occur. Nasal stuffiness due to mastoid and paranasal sinus malformation is often the presenting feature of infantile osteopetrosis. Cranial nerve entrapment neuropathies occur due to failure of the foramina in the skull to widen completely. Manifestations include deafness, proptosis, and hydrocephalus. Dentition might be delayed. Osteomyelitis of the mandible is common due to a deficient blood supply. Bones are fragile and can fracture easily. Defective osseous tissue tends to replace bone marrow, which can cause bone marrow failure with resultant pancytopenia. Patients might have anemia, easy bruising and bleeding (due to thrombocytopenia), and recurrent infections (due to inherent defects in the immune system). Extramedullary hematopoiesis might occur with resultant hepatosplenomegaly, hypersplenism, and hemolysis. Other manifestations include sleep apnea and blindness due to retinal degeneration.

Adult osteopetrosis (also called benign osteopetrosis) is diagnosed in late adolescence or adulthood. Approximately one half of the patients are asymptomatic, and the diagnosis is made incidentally (often in late adolescence because radiological abnormalities start appearing only in childhood) or is based on family history. Other patients might present with osteomyelitis or fractures. Many patients have bone pain. Bony defects are common and include cranial nerve entrapment neuropathies (e.g. with deafness, with facial palsy), carpal tunnel syndrome, and osteoarthritis. Bones are fragile and might fracture easily. Approximately 40% of patients have recurrent fractures. Osteomyelitis of the mandible occurs in 10% of patients. Bone marrow function is not compromised. Other manifestations include visual impairment due to retinal degeneration and psychomotor retardation. Physical findings are related to bony defects and include short stature, frontal bossing, a large head, nystagmus, hepatosplenomegaly, and genu valgum in infantile osteopetrosis. The differential diagnoses include hypoparathyroidism, myeloproliferative disease, Paget’s disease, pseudohypoparathyroidism and lead toxicity.

Oral Manifestations

The jaws are involved in the same manner as the other bones in the body, and the oral manifestations have been reviewed by Kaslick and Brustein. However, a clear distinction has usually not been made as to the type of the disease present, benign or malignant. The medullary spaces of the jaws are remarkably reduced in both dominant and recessive osteopetrosis so that there is a marked predilection for the development of osteomyelitis should infection gain entrance to the bone. This is a complication of dental extraction which has been reported frequently and discussed by Dyson. Similar findings were noted by Bjorvatn and his associates in four children with the malignant form of the disease. They stressed the necessity of administering large doses of antibiotics to control the recurring infection, which even then did not prevent the progressive osseous destruction. Fracture of the jaw during tooth extraction, even when the extraction is performed without undue force, may also occur because of the fragility of the bone. It has been reported that the teeth are of defective quality, enamel hypoplasia, microscopic dentinal defects and arrested root development all having been described. However, this may not be true in the benign dominant form of the disease. It is also reported that the teeth are especially prone to dental caries. Since dental findings have been recorded in so few cases, this observation is difficult to evaluate. An additional rather constant finding is retardation of tooth eruption due to the sclerosis of bone.

Radiographic Features

Radiographic features are usually diagnostic. Because the disease is a heterogeneous group of disorders, the findings vary depending on the subtype. Patients usually have generalized osteosclerosis. Bones may be uniformly sclerotic, but alternating sclerotic and lucent bands may be noted near the ends of long bones (Fig. 17-6). The bones might appear club like or show an appearance of a bone within bone (endobone). The entire skull is thickened and dense, especially at the base. Sinuses are small and underpneumatized. Vertebrae are extremely radiodense. They may show alternating bands, known as the ‘rugger-jersey’ sign. Radiographs may show evidence of fractures or osteomyelitis. When the jaws are affected, the density of the bone may be such that the roots of the teeth are nearly invisible on the dental radiograph.

Laboratory Findings

The patients manifest a myelophthisic anemia due to the displacement of hematopoietic marrow tissue by bone. Hypocalcemia can occur and cause rickets if it is severe enough. Parathyroid hormone (PTH) is often elevated (secondary hyperparathyroidism). Acid phosphatase and creatinine kinase (CK-BB) levels are increased due to increased release from defective osteoclasts.

Histologic Features

Bone biopsy is not essential for diagnosis because radiographs are usually diagnostic. Osteopetrosis is characterized by the endosteal production of bone with an apparent concomitant lack of physiologic bone resorption (Fig. 17-7). Osteoblasts are prominent, but osteoclasts are seldom found in significant numbers in tissue sections. The predominance of bone formation over resorption typically leads to the persistence of cartilaginous cores of bony trabeculae long after their replacement should have occurred in endochondral bones. The trabeculae themselves are disorderly in arrangement, and the marrow tissue present is usually fibrous.

It has been reported by Johnston and his associates; however, that adult patients with benign osteopetrosis do not appear to have a deficiency in osteoclastic activity but rather an abnormality in the type and structure of bone. They found osteoblastic and osteoclastic activity with prominent remodeling of bone. However, by polarized light, the bone was found to be markedly deficient in collagen matrix fibrils and these seldom crossed from one osteon to another. This deficiency of fibrils could account for the tendency for fracture in these patients.

Treatment and Prognosis

Infantile osteopetrosis warrants treatment due to the adverse outcome associated with the disease. Calcitriol appears to help by stimulating dormant osteoclasts, and thus, stimulating bone resorption. Erythropoietin can be used to correct anemia. Corticosteroids have been used with the hope of stimulating bone resorption and treating the anemia. Treatment with gamma interferon has been shown to produce long-term benefits. Adult osteopetrosis requires no treatment by itself, though complications of the disease might require intervention. No specific medical treatment exists for the adult type. If untreated, infantile osteopetrosis usually results in death by the first decade of life due to severe anemia, bleeding, or infections. Patients fail to survive, have growth retardation, and increased morbidity. Prognosis can change remarkably in some patients after bone marrow transplantation. Patients with adult osteopetrosis have good long-term survival rates.

• Autosomal dominate type (nonrhizomelic)

• Autosomal recessive type (rhizomelic)

• X-linked dominant type

• X-linked recessive type

• Sheffield, mild type

• Other variants.

Radiographic Features

Mild shortening of all long bones with multiple epiphyseal punctate calcific deposits in the infantile cartilaginous skeleton, which may or may not be seen by ultrasound after 14 weeks. Vertebral body deformities and scoliosis can also be seen. Stippling of the proximal humerus may also help to identify the condition.

Prognosis

The prognosis is excellent. Affected individuals usually have a normal life span and intelligence.

Clinical Features

This dysplasia is characterized by a short-limbed stature. There is hypoplasia or absence of the lateral portion of the clavicles, and hypoplasia of the terminal phalanges of the digits (termed acro-osteolysis), leading to short, stubby hands with large finger nails. The skull has widened sutures and persistent open fontanels, even into adulthood. The mandible is small, and the angle of the mandible is obtuse, leading to a very small chin. The nose is protuberant. The teeth are delayed in appearance and disordered when present.

Radiographic Features

Radiographs show generalized osteosclerosis. The medullary canal is always present, but it is small and irregular. The sclerotic bone has a propensity to fracture, with fractures generally occurring in the lower extremities. Bone formation and resorption are simultaneously diminished. MRI studies have shown the cortex to be of normal thickness, whereas the space within the medullary canal was limited as a result of the increase in trabecular bone. Bone scan reveals increased uptake.

Histologic Features

Microscopic examination of bone biopsy specimens are similar to those in osteopetrosis. Meredith and associates (1978) proposed that normal osteoblasts and osteoclasts fail to respond as they should to the demands of stress on the bone. Although osteoclast are present, they do not appear to function properly in resorbing bone. At fracture sites, all cellular elements of fracture repair are present.

The differential diagnosis includes osteopetrosis. Unlike osteopetrosis, pyknodysostosis does not lead to aplastic anemia, because the medullary canal is partially preserved. Cleidocranial dysostosis may be considered because of the hypoplasia of the clavicles; however, osteosclerosis is not seen in cleidocranial dysostosis.

Treatment and Prognosis

Orthopedic treatment consists of fracture care. Life expectancy is normal. Chronic osteomyelitis of the jaw occurs frequently and is resistant to standard forms of treatment.

Etiology

Glycosaminoglycans (GAG) are long, linear polysaccharide molecules composed of repeating dimers, each of which contains a hexuronic acid (or galactose in the case of keratan sulfate) and an amino sugar. The large proteoglycan molecules made up of protein cores and GAG branches are secreted by cells and constitute a significant fraction of the extracellular matrix of the connective tissue. The turnover of these molecules depends on their subsequent internalization by endocytosis, their delivery to the lysosomes, and their digestion by lysosomal enzymes. The enzyme deficiencies lead to the accumulation of mucopolysaccharides in the lysosomes of the cells in the connective tissue and to an increase in their excretion in the urine.

Clinical Features

Onset usually occurs in early childhood. Skeletal findings include dwarfism, with rather characteristic radiologic changes of the hands and the lumbar vertebral column; stiff articulations; and coarse facies. Patients with Hurler syndrome usually die by the time they are aged 5–10 years. The life expectancy of patients with Scheie syndrome may be nearly normal. They can live until the fifth or sixth decade of life, and they can have healthy offspring. As for patients with Hunter and Sanfilippo syndrome, death usually occurs by the time of puberty. In the classic form of Morquio syndrome, long-term survival is rare, with death occurring in persons aged 20–40 years. In patients with the severe form of Maroteaux-Lamy syndrome, death usually occurs by early adulthood.

Differential diagnoses include Gaucher disease, NiemannPick disease, syphilis, osteogenesis imperfecta, vitamin D-resistant rickets, nephrogenic osteopathy, spondyloepiphysial dysplasia, metaphysial dysplasia.

Treatment

No cure for MPS exists, treatment is symptomatic and supportive. However, possible treatments are being investigated in several clinical trials.

Etiology

Rickets results either from a deficiency or abnormal metabolism of vitamin D or from abnormal metabolism or excretion of inorganic phosphate. Histologic changes are seen at the level of the growth plates, or more specifically, at the level of the hypertrophic zone, where an increased number of disorganized cells is found. The increased number of cells results in increased width and thickness of the hypertrophic zone (rachitic metaphysis).

In most developing countries, rickets is seldom seen, supposedly due to high exposure to sunlight. An exception occurs in groups of women who are rarely allowed to leave the house (largely for religious reasons) or who must wear veils when they do. Since these women may have low vitamin D levels, their babies are at a higher risk of developing rickets. When patients receive adequate treatment, no mortality is associated with this disease; however concomitant diseases, such as pneumonia, tuberculosis, and enteritis, occur with a higher frequency and may cause death. Boys and girls are affected equally with rickets. There is a form of genetic rickets, called X-linked hypophosphatemic rickets, in which some children, often girls, may be only moderately affected, although girls with X-linked hypophosphatemic rickets can have rickets symptoms that are just as severe as those in boys. By definition, rickets occurs only in children whose growth plates have not closed. The growth plates close at the end of puberty, at approximately age of 17 years in females and age of 19 years in males. Premature neonates are especially at risk because their requirements for vitamin D, calcium, and phosphate are higher than the requirements in full-term neonates (for details, refer to Chapter 15 on Oral Aspects of Metabolic Disease).

Etiology

In 85% of affected persons, primary hyperparathyroidism results from an adenoma in a single parathyroid gland. Hypertrophy of the parathyroid glands causes hyperparathyroidism in 15% of patients. Parathyroid malignancies account for a small number of hyperparathyroidism cases. Hyperparathyroidism is common in patients with type I and type II multiple endocrine neoplasia (MEN) and in patients who received radiation therapy to the head and neck during childhood for benign diseases. Also, a syndrome of familial hyperparathyroidism has been observed. Secondary hyperparathyroidism occurs when the parathyroid glands become hyperplastic after long-term stimulation to release PTH in response to chronically low serum calcium. Chronic renal failure, rickets, and malabsorption syndromes are the most frequent causes. In secondary hyperparathyroidism, high levels of PTH do not cause hypercalcemia because the primary problem makes calcium unavailable. With long-term hyperstimulation, the glands eventually function autonomously and continue to produce high levels of parathyroid hormone even after the chronic hypocalcemia has been corrected. Hypercalcemia caused by autonomous parathyroid function after long-term hyperstimulation is referred to as tertiary hyperparathyroidism.

Clinical Features

Of the endocrine disorders, only diabetes mellitus and hyperthyroidism occur more frequently than hyperparathyroidism. Hereditary hyperparathyroidism occurs most frequently as part of a syndrome of multiple endocrine neoplasia (MEN). MEN 1 consists of hyperparathyroidism with tumors of the pituitary and pancreas. MEN 2A consists of hyperparathyroidism, pheochromocytoma, and medullary carcinoma of the thyroid. Although hyperparathyroidism can occur at any age, it is most common in the fifth and sixth decades of life. Prevalence is higher in females than in males, with a male-to-female ratio of approximately 1 : 2. At least one half of patients with hyperparathyroidism are asymptomatic. Manifestations of hyperparathyroidism may be subtle, and the disease may run a benign course for many years. Less commonly, hyperparathyroidism may worsen abruptly and cause severe hypercalcemic complications (e.g., profound dehydration, coma). This is referred to as hypercalcemic parathyroid crisis.

The skeletal and neuromuscular changes manifest as bone pain and/or tenderness, muscle fatigue, weakness and spontaneous fractures; nonspecific myalgias, osteoporosis, osteopenia, cystic bone lesions, vertebral collapse, chondrocalcinosis and pseudogout can develop. Patients have a tendency to develop pancreatitis and/or pancreatic calcification and peptic ulcer disease which can result in abdominal distress, constipation, vomiting, anorexia and weight loss. Neuropsychiatric illness and altered mental status such as anxiety, depression, psychosis and apathy have been reported. Signs of hypertension and congestive heart failure may be apparent.

Radiographic Features (Refer to Chapter 15)

Laboratory Findings

The diagnosis of hyperparathyroidism is made by demonstrating elevated parathyroid hormone levels in the setting of high serum calcium. Almost all other causes of hypercalcemia suppress the release of parathyroid hormone, which is measured by radioimmunoassay. Other findings include elevated serum chloride levels, decreased serum phosphate level (less than 2.5 mg/dl (0.81 mmol/L), decreased serum carbon dioxide, hyperchloremic metabolic acidosis, increase in urine cyclic adenosine monophosphate (cAMP).

Histologic Features (Refer to Chapter 15)

Treatment and Prognosis

The emergency management of hyperparathyroidism is focused on the treatment of the hypercalcemia. Specifically, the goal of treatment is to reduce the calcium level to below 11.5 mg/dl, less than the level in which most patients have resolution of hypercalcemia-induced symptoms.

Clinical Features

The signs and symptoms of hypoparathyroidism include evidence of latent or overt neuromuscular hyperexcitability due to hypocalcemia. The effect may be aggravated by hyperkalemia or hypomagnesemia, but there is wide variation in the severity of the symptoms. Patients may complain of circumoral numbness, paresthesia of the distal extremities or muscle cramping which can progress to carpopedal spasm or tetany. Laryngospasm or bronchospasm and seizures may also occur. Other less specific manifestations include fatigue, irritability, and personality disturbance. Patients with chronic hypocalcemia may have calcification of the basal ganglia or more widespread intracranial calcification, detected by skull X-ray or CT scan. Also seen are extrapyramidal neurological symptoms (more often with intracranial calcification), subcapsular cataracts, band keratopathy, and abnormal dentition.

In hypoparathyroidism, serum calcium concentrations are decreased and serum phosphate levels are increased. Serum PTH is low or undetectable (the important exception is PTH resistance—pseudohypoparathyroidism—discussed below). Usually, serum 1,25(OH)2D is low, but alkaline phosphatase activity is normal. Despite an increase in fractional excretion of calcium, intestinal calcium absorption and bone resorption are both suppressed. The renal filtered load of calcium is decreased, and the 24-hour urinary calcium excretion is reduced; nephrogenous cyclic AMP excretion is low and renal tubular reabsorption of phosphate is elevated. After parenteral administration of biologically active PTH, plasma and urinary cyclic AMP and inorganic phosphate excretion increase — a test (the EllsworthHoward test) that differentiates hypoparathyroidism from pseudohypoparathyroidism. Hypoparathyroidism is a feature common to various kinds of inherited disorders. Although familial occurrences are reported, sporadic cases are common. Autoimmune hypoparathyroidism can occur as an isolated endocrine condition or with other glandular deficiencies in a pluriglandular autoimmune syndrome, and it can occur as a congenital hypoplasia/aplasia with or without other congenital anomalies such as lymphedema, nephropathy, nerve deafness or cardiac malformation. It also occurs as an isolated finding.

Autoimmune parathyroid gland ablation or destruction

Antibodies directed against parathyroid tissue have been detected in over 30% of patients with isolated hypoparathyroid disease, and over 40% of patients having hypoparathyroidism combined with other endocrine deficiencies. It remains to be seen whether the autoantibodies are of primary or secondary importance in these cases.

Pseudohypoparathyroidism

Several clinical disorders characterized by end-organ resistance to PTH have been described collectively by the term pseudohypoparathyroidism (PHP). They are associated with hypocalcemia, hyperphosphatemia, and increased circulating PTH, but target tissue unresponsiveness to the hormone manifests as a lack of increased cAMP excretion in response to PTH administration.

Treatment

The goal of treatment in hypoparathyroid state is to raise the serum calcium sufficiently to alleviate acute symptoms and prevent the complications of chronic hypocalcemia. The calcium concentration required for this purpose is generally the low-normal range. Acute or severe symptomatic hypocalcemia is best treated with intravenous calcium infusion. Initial doses of 2–5 millimoles of elemental calcium as the gluconate salt can be given over a 10–20 minute period, followed by 2 millimoles elemental calcium per hour as a maintenance dose, to be adjusted according to symptoms and biochemical response.

Etiology

The exact cause of fibrous dysplasia is not known. The condition is not believed to be hereditary. Fibrous dysplasia is usually caused by a mutation in the GNAS1 gene (20q13.2). The GNAS1 (guanine nucleotide-binding protein, α-stimulating activity polypeptide) gene encodes a G-protein that stimulates the production of cAMP. The mutation results in a continuous activation of the G-protein leading to overproduction of cAMP in affected tissues. This results in a hyperfunction of affected endocrine organs, frequently giving rise to precocious puberty, hyperthyroidism, growth hormone and cortisol overproduction. Secondly, there is an increased proliferation of melanocytes resulting in large café-au-lait spots with irregular margins as opposed to the regular outlined café-au-lait spots in neurofibromatosis. Thirdly, cAMP is thought to have an effect on the differentation of osteoblasts leading to fibrous dysplasia. In fibrous dysplasia, the medullary bone is replaced by fibrous tissue, which appears radiolucent on radiographs, with the classically described ground-glass appearance. Trabeculae of woven bone contain fluid-filled cysts that are embedded largely in collagenous fibrous matrix, contributes to the generalized hazy appearance of the bone.

Clinical Features

The following three disease patterns are recognized:

The initial manifestations of fibrous dysplasia are most commonly found in persons aged 3–15 years. Two-thirds of patients with polyostotic disease are asymptomatic before they are aged 10 years. With monostotic disease, patients as old as 20 or 30 years are asymptomatic. No specific racial predilection exists. The incidence is equal in males and females. Clinical findings of increasing pain and an enlarging soft tissue mass suggest malignant change.

Radiographic Features

The usual appearance of fibrous dysplasia in long and short tubular bones includes a lucent lesion in the diaphysis or metaphysis, with endosteal scalloping and with or without bone expansion and the absence of periosteal reaction. The lucent lesion has a thick sclerotic border and is called the rind sign. Among skull and facial bones the frontal bone is involved more frequently than the sphenoid, with obliteration of the sphenoid and frontal sinuses. Single or multiple, symmetric or asymmetric, radiolucent or sclerotic lesions in the skull or facial bones may be present. Most commonly, maxillary and mandibular involvement has a mixed radiolucent and radiopaque pattern, with displacement of the teeth and distortion of the nasal cavities.

Oral Manifestations

The oral manifestations of polyostotic fibrous dysplasia are related to the severe disturbance of the bony tissue. One-third of the polyostotic patients in the series of Van Horn and his associates had lesions in the mandible. The occurrence of maxillary lesions was not mentioned, although Harris and his group stated that maxillary and mandibular involvement was not rare.

There may be expansion and deformity of the jaws, and the eruption pattern of the teeth is disturbed because of the loss of normal support of the developing teeth. The endocrine disturbance also may alter the time of eruption of the teeth. A classic case with involvement of the maxilla has been reported by Church. In this instance there was no intraoral pigmentation, although it has been reported to occur.

Histologic Features

The lesions are composed of fibrillar connective tissue within which are numerous trabeculae of coarse, woven immature bone, irregular in shape but evenly spaced, showing no relation to functional patterns. The osteocytes are quite large, and collagen fibers of these trabeculae can often be seen extending out into the fibrous tissue. Bone formation by stellate osteoblasts can be observed, although rows of cuboidal osteoblasts lined up on the surfaces of trabeculae are absent (osteoblastic riming). These trabeculae typically have wide osteoid seams. Osteoclastic activity may be seen where the calcification of osteoid extends to the surface of the trabeculae.

Treatment and Prognosis

Treatment is usually conservative and primarily to prevent deformity. Any underlying endocrine disturbances should be treated. In upper extremity lesions, more than 80% respond to nonsurgical management. No specific medical treatment exists for the bone disease, although early evidence suggests that vitamin D and bisphosphonates (after epiphyseal closure) may be helpful in ameliorating pain and possibly in reconstituting lesions with normal bone. Surgical therapy with curettage and replacement of the bone defect with autograft or allograft usually results in resorption of the graft at the surgical site. Use of allograft or cortical autograft usually delays this conversion, as it is more resistant to resorption and replacement by dysplastic bone.

Of special concern is malignant degeneration and metabolic changes in patients with fibrous dysplasia. The estimated frequency of malignant transformation is 0.4–1% in fewer than 50 reported cases. The interval from the diagnosis of fibrous dysplasia to the development of malignancy varies and is usually years or decades. Most often, skull and facial bones undergo malignant change in monostotic disease, whereas femoral and facial bones undergo malignant change in polyostotic disease. Osteosarcoma and fibrosarcoma are the most common tumors. Chondrosarcomas occur less frequently. Radiographic features suggestive of malignant degeneration include a rapid increase in the size of the lesion and a change from a previously mineralized bony lesion to a lytic lesion. Clinical findings of increasing pain and an enlarging soft tissue mass suggest malignant change.

Clinical Features

Monostotic fibrous dysplasia of the jaws occurs with apparently equal predilection for males and females, although some reports show a mild predominance of females. It is more common in children and young adults than in older persons. The mean age of occurrence in the 69 patients reported by Zimmerman and his associates was 27 years, while in 53 patients with craniofacial fibrous dysplasia reported by Gardner and Halpert, the mean age was 34 years.

The first clinical sign of the disease is a painless swelling or bulging of the jaw. The swelling usually involves the labial or buccal plate, seldom the lingual aspect, and when it involves the mandible it sometimes causes a protuberant excrescence of the inferior border. There may be some malalignment, tipping or displacement of the teeth due to the progressive expansile nature of the lesion, and tenderness may ultimately develop. The mucosa is almost invariably intact over the lesion.

Fibrous dysplasia of the maxilla is an especially serious form of the disease since it has a marked predilection for occurrence in children and is almost impossible to eradicate without radical, mutilating surgery (Fig. 17-8). These lesions are not well circumscribed, commonly extend locally to involve the maxillary sinus, the zygomatic process and the floor of the orbit, and even extend back toward the base of the skull. Severe malocclusion and bulging of the canine fossa or extreme prominence of the zygomatic process, producing a marked facial deformity, are typical sequelae of this disease in this location need not be truly monostotic, but neither is it usually classified as a polyostotic type. It has sometimes been referred to as craniofacial fibrous dysplasia, since it does affect the craniofacial complex and is so characteristic in its clinical and radiographic features that it closely resembles a distinct entity (Fig. 17-9). This form of the disease has been described in detail by Waldron and Giansanti and by Eversole and his associates.

Radiographic Features

The radiographic appearance of fibrous dysplasia of the jaw is extremely variable (Fig. 17-10). There are three basic patterns which may be seen. In one type, the lesion is generally a rather small unilocular radiolucency or a somewhat larger multilocular radiolucency, both with a rather well-circumscribed border and containing a network of fine bony trabeculae. In the second type, the pattern is similar except that increased trabeculation renders the lesion more opaque and typically mottled in appearance. The third type of quite opaque with many delicate trabeculae gives a ‘ground-glass’ or ‘peau d’orange’ appearance to the lesion. This latter type characteristically is not well circumscribed but instead blends into the adjacent normal bone. Any of the three types may be found in either maxilla or mandible. In all types, generally the cortical bone becomes thinned because of the expansile nature of the growth, but seldom is this bony plate perforated, or is periosteal proliferation obvious. The roots of teeth in the involved areas may be separated or moved out of normal position but only occasionally exhibit severe resorption. In some cases, the bone appears so opaque that the roots of teeth may be indistinct or not visible.

It is of interest that, in craniofacial fibrous dysplasia, there is characteristic radiographic thickening of the base of the skull.

Histologic Features

There is considerable microscopic variation in cases of monostotic fibrous dysplasia of the jaws. The lesion is essentially a fibrous one made up of proliferating fibroblasts in a compact stroma of interlacing collagen fibers (Fig. 17-11A, B). Irregular trabeculae of bone are scattered throughout the lesion with no definite pattern of arrangement. Characteristically, some of these trabeculae are C-shaped, or as described by one author, Chinese character-shaped. These trabeculae are usually coarse woven bone but may be lamellar, although not as well organized as normal lamellar bone. The relationship of osteoblasts and osteoclasts to the trabeculae is similar to that seen in the polyostotic form of the disease. Large lesions may show variation from area to area and sometimes present a greater bony reaction around the periphery of the lesion than in the central portion.

Some of the earlier literature dealing with this disease suggested that it represents a permanent maturation arrest in the woven bone stage and proposed that lesions demonstrating lamellar bone transformation should not be diagnosed as fibrous dysplasia. However, it is generally well accepted now, particularly on the basis of the work of Waldron and Giansanti, that lesions of fibrous dysplasia of the jaws, especially the craniofacial type, will mature over a period of time and the lesional tissue may show lamellar bone.

Clinical Features

Precocious puberty associated with the condition is gonadotrophin-independent. Among the endocrine disturbances described in association with Albright syndrome are:

Some severely affected patients may present with associated hepatic, cardiac, and GI dysfunction (i.e. elevated hepatic transaminases, GI polyposis, and cardiomyopathy).

Cutaneous pigmentation is the most common extraskeletal manifestation in fibrous dysplasia and occurs in more than 50% of cases of the polyostotic form. Cutaneous pigmentation in polyostotic fibrous dysplasia is ipsilateral to the side of bony lesions, a feature that differentiates this disease from pigmentation in neurofibromatosis. The pigmented macules or café-au-lait spots (Fig. 17-12) are related to increased amounts of melanin in the basal cells of the epidermis. They tend to be arranged in a linear or segmental pattern near the midline of the body, usually overlying the lower lumbar spine, sacrum, buttocks, upper back, neck, and shoulders. Similar lesions may occur on the lips and oral mucosa. Pigmentation may occur at birth, and in fact, they occasionally precede the development of skeletal and endocrine abnormalities.

The association of fibrous dysplasia and intramuscular myxoma is a rare disease known as Mazabraud’s syndrome. Both lesions tend to occur in the same anatomical region. The relationship between fibrous dysplasia and myxoma remains unclear, whereas an underlying localized error in tissue metabolism has been proposed to explain this occasional coexistence. Patients with soft tissue myxomas should be thoroughly examined for fibrous dysplasia. The greater risk of sarcomatous transformation in fibrous dysplasia with Mazabraud’s syndrome has been reported.

Only a few cases of malignant transformation of skeletal lesions have been described in the setting of McCune-Albright syndrome. Malignancies described in this include:

These malignancies occur most commonly in the setting of therapeutic irradiation exposure. Females may have a greater risk for breast cancer, probably due to their prolonged exposure to elevated estrogen levels. The underlying GS alpha gene mutation also may play a role in this. For the same reasons, these patients also appear to be at an increased risk of thyroid and secondary osseous malignancies. Hypophosphatemic rickets is another potential complication that may worsen the bone disease associated with polyostotic fibrous dysplasia. While on vitamin D and phosphorus supplements, patients with McCune-Albright syndrome and hypophosphatemic rickets must be monitored closely for hypercalcemia and secondary hyperparathyroidism.

Laboratory Findings

There are no consistent significant changes in the serum calcium or phosphorus, although the serum alkaline phosphatase level is sometimes elevated. Premature secretion of pituitary follicle-stimulating hormone has been reported, as well as moderately elevated basal metabolic rate.

Histologic Findings

The bone affected by polyostotic fibrous dysplasia has areas of fibrous metaplasia within flat and tubular bones. The basic anomaly in fibrous dysplasia lesions is a progressively expanding fibrous lesion of bone-forming mesenchyme. The lesions typically expand concentrically from the medullary cavity outwards (i.e. towards the cortex). The bony lesions are well defined, although invariably not encapsulated. The lesions are rich in spindle-shaped fibroblasts, with a swirled appearance within the marrow space and erratically arranged ‘tongues’ of woven bone. Islands of cartilaginous tissue also may be interspersed within the lesions. Some parts of the affected bones may have cystic lesions lined by multinucleated giant cells akin to ostitis fibrosa cystica (of severe hyperparathyroidism) but with a paucity of osteoblasts.

Treatment and Prognosis

McCune-Albright syndrome is a multisystem condition with a host of variable presentations. Management often is challenging and requires a multidisciplinary approach. Apart from the small subgroup of patients that has increased mortality and those who develop malignancies, McCune-Albright syndrome is not associated with a significantly increased mortality risk. Deformities associated with polyostotic fibrous dysplasia result in variable degrees of morbidity, ranging from mild to very severe.

Genetics

Mutations in the SH3BP2 (SH3 domain binding protein 2) gene have been identified in about 80% of people with cherubism. In most of the remaining cases, the genetic cause of the condition is unknown.

The SH3BP2 gene provides instructions for making a protein whose exact function is still unclear. The protein plays a role in transmitting chemical signals within cells, particularly cells involved in the replacement of old bone tissue with new one (bone remodeling) and certain immune system cells.

Mutations in the SH3BP2 gene lead to the production of an overactive version of this protein which is expected to disrupt critical signaling pathways in cells associated with the maintenance of bone tissue and some immunologic effecter cells. The overactive protein likely causes inflammation in the jaw bones and triggers the production of osteoclasts, which cause breakage of bone tissue while remodeling. A combination of bone loss and inflammation likely underlies the cyst-like growths characteristic of cherubism. Atleast 11 mutations in the SH3BP2 gene have been identified in people with cherubism.

Clinical Features

Affected children are normal at birth and are without clinically or radiographically evident disease until 14 months to 3 years of age. At that time, symmetric enlargement of the jaws begins. Typically, the earlier the lesion appears, the more rapidly it progresses. The self-limited bone growth usually begins to slow down when the patient reaches five years of age, and stops by the age of 12–15 years. At puberty the lesions begin to regress. Jaw remodeling continues through the third decade of life, at the end of which the clinical abnormality may be subtle. The signs and symptoms depend on the severity of the condition and range from clinically or radiographically undetectable features to grotesquely deforming mandibular and maxillary overgrowth with respiratory obstruction and impairment of vision and hearing. The jaw lesions are usually painless and symmetric and have florid maxillary involvement. The lesions, which are firm to palpation and nontender, most commonly involve the molar to coronoid regions, the condyles always being spared, and are often associated with cervical lymphadenopathy. Enlargement of the cervical lymph nodes contributes to the patient’s full-faced appearance and is said to be caused by lymphoid hyperplasia with fibrosis. The lymph nodes become enlarged before the patient reaches 6 years of age, decrease in size after the age of 8 years and are rarely enlarged after the age of 12 years. Intraoral swelling of the alveolar ridges may occur. When the maxillary ridge is involved, the palate assumes a V shape. A rim of sclera may be visible beneath the iris, giving the classic ‘eye to heaven’ appearance.

Oral Manifestations

Numerous dental abnormalities have been reported, such as agenesis of the second and third molars of the mandible, displacement of the teeth, premature exfoliation of the primary teeth, delayed eruption of the permanent teeth, and transpositions and rotation of the teeth. In severe cases, tooth resorption occurs. Although cherubism was initially described as a familial disease affecting the jaws, cases without any apparent hereditary origin have been reported. In a few cases, cherubism has been described as being connected with other diseases and conditions such as Noonan’s syndrome, a lesion in the humerus, gingival fibromatosis, psychomotor retardation, orbital involvement and obstructive sleep apnea. The deciduous dentition may be shed prematurely, beginning as early as 3 years of age. The permanent dentition is often defective, with absence of numerous teeth and displacement and lack of eruption of those present. The oral mucosa is usually intact and of normal color.

Grading System

Arnott (1978) suggested the following grading system for the lesions of cherubism: grade I is characterized by involvement of both mandibular ascending rami, grade II by involvement of both maxillary tuberosities as well as the mandibular ascending rami, and grade III by McCuneAlbright syndrome involvement of the whole maxilla and mandible except the coronoid process and condyles.

Radiographic Features

Radiologically, cherubism is characterized by bilateral multilocular cystic expansion of the jaws. Early lesions occur in the posterior body of the mandible and the ascending rami. Maxillary lesions may occur at the same time but escape early radiographic detection because of overlap of the sinus and nasal cavities. Displacement of the inferior alveolar canal has been reported. The presence of numerous unerupted teeth and the destruction of the alveolar bone may displace the teeth, producing a radiographic appearance referred to as floating tooth syndrome (Fig. 17-14). With adulthood, the cystic areas in the jaws become re-ossified, which results in irregular patchy sclerosis. There is a classic (but nonspecific) ground glass appearance because of the small, tightly compressed trabecular pattern.

Histologic Features

Histologic examination of the lesions usually reveals numerous multinucleated giant cells. These multinucleated cells show strong positivity for tartrate-resistant acid phosphatase, which is characteristic of osteoclasts. The collagenous stroma, which contains a large number of spindleshaped fibroblasts, is considered unique because of its waterlogged, granular nature. Numerous small vessels are present, and the capillaries exhibit large endothelial cells and perivascular cuffing. The eosinophilic cuffing appears to be specific to cherubism. However, these deposits are not present in many cases, and their absence does not exclude the diagnosis of cherubism. Older, resolving lesions of cherubism show an increase in fibrous tissue, a decrease in the number of giant cells and formation of new bone. The microscopic findings seldom permit a specific diagnosis of cherubism in the absence of clinical and radiological information.

The differential diagnoses of cherubism consist of giant cell granuloma of the jaws, osteoclastoma, aneurysmal bone cyst, fibrous dysplasia and hyperparathyroidism.

Treatment

As Laskin (1985) stated, “the treatment of cherubism should be based on the known natural course of the disease and the clinical behavior of the individual case”. Therefore, surgery to correct the jaw deformities of cherubism is rarely indicated. If necessary, surgery is usually undertaken after puberty, when the remission phase of the lesions have been reached, unless esthetic considerations or severe functional problems justify earlier treatment. Although exacerbation has sometimes been reported after surgery, it is believed that surgery ultimately accelerates the involution process.

Etiology

Several of the most vexing questions about the underlying mechanism causing the clinical phenotype of X-linked hypophosphatemia remain unanswered. Great strides have been made in recent years, particularly with the cloning of the mutant gene known as PEX. This gene, found on the X chromosome, is thought to produce a currently unknown hormone involved in phosphate regulation. The gene for hypophosphatemic rickets has been localized. The X-linked dominant form of the disease is attributed to mutations in the PEX gene, located at Xp22.1. The gene locus for autosomal dominant hypophosphatemic rickets has been located on chromosome 12p13. The pathogenesis of this disorder is clear; phosphate wasting at the proximal tubule level is the basis of the affected individual’s inability to establish normal ossification. This phenomenon is secondary to defective regulation of the sodium-phosphate cotransporter in the epithelial cell brush border. Normal phosphate reabsorption in response to 1,25-dihydroxycholecalciferol (calcitriol) provides clear evidence that the sodium-phosphate cotransporter is capable of proper function and is not intrinsically defective.

Clinical Features

As in all genetic disorders, the disease is present from conception. Affected newborns are of normal weight, but infants may show growth retardation. Intellectual development is unaffected. Although serum phosphate levels are depressed similarly in affected males and females, the degree of bone involvement is substantially less severe in heterozygous females. All hemizygous males are clinically affected. Widened joint spaces and flaring at the knees may become apparent in children by their first birthday, particularly in boys. When a child begins to stand and walk, bowing of the weight-bearing long bones quickly becomes clinically evident. Dentition may be absent or delayed in very young children due to abnormal tooth formation; older children may experience multiple dental abscesses.

Laboratory Findings

Laboratory evaluation of rickets begins with assessment of serum calcium, phosphate, and alkaline phosphatase levels. In hypophosphatemic rickets, calcium levels may be within or slightly below reference ranges; alkaline phosphatase levels are significantly above reference ranges. Serum phosphate levels must be carefully evaluated in the first year because the concentration reference range for infants (5.0–7.5 mg/dl) is high compared to adults (2.7–4.5 mg/dl). Hypophosphatemia can be missed easily in a baby. Serum parathyroid hormone level is within reference ranges to slightly elevated, while calcitriol level is low or in the lower reference range. Most importantly, urinary loss of phosphate is above reference ranges.

Radiographic Features

In all cases of rickets, the study of choice is radiography of the wrists, knees, ankles, and long bones. No pathognomonic sign on X-ray distinguishes hypophosphatemic rickets from other variants of rickets.

Oral Manifestations (Refer to Chapter 15)

Histologic Features (Refer to Chapter 15)

Treatment and Prognosis

Treatment can be administered safely on an outpatient basis, although serum calcium concentrations must be monitored periodically and carefully. Conscientious follow-up is essential. The usual vitamin D preparations are not useful for treatment in this disorder because they lack significant 1-alpha-hydroxylase activity. Original treatment protocols advocated vitamin D at levels of 25,000–50,000 U/d (at the lower limit of toxic dosage), which placed the patient in jeopardy of frequent hypercalcemic episodes. Now more widely available, calcitriol substantially diminishes but does not eliminate this risk. Amiloride and hydrochlorothiazide are administered to enhance calcium reabsorption and to reduce the risk of nephrocalcinosis. Surgical care involves osteotomy to realign extremely distorted leg curvatures in children whose diagnosis was delayed or whose initial treatment was inadequate. Skull deformity may require treatment for synostosis. Spontaneous abscesses often require periodic dental procedures. Apart from the short stature of most affected adults, the prognosis for a normal lifespan and normal health is good.

Etiology

Multiple theories have been proposed for the etiology of primary craniosynostosis, but the most widely accepted is a primary defect in the mesenchymal layer ossification in the cranial bones. Secondary craniosynostosis typically results from systemic disorders such as endocrine disorders, hypothyroidism, hypophosphatemia, vitamin D deficiency, renal osteodystrophy, hypercalcemia, and rickets; hematologic disorders that cause bone marrow hyperplasia (e.g. sickle cell disease, thalassemia) and inadequate brain growth, including microcephaly and its causes.

The syndromic causes appear to result from genetic mutations responsible for fibroblast growth factor receptors 2 and 3. A gene locus for single suture craniosynostosis has not been identified. Primary craniosynostosis results when one or more sutures fuse prematurely, skull growth can be restricted perpendicular to the suture. If multiple sutures fuse while the brain is still increasing in size, intracranial pressure can increase. Secondary craniosynostosis is more frequent than the primary type, and results from early fusion of sutures due to primary failure of brain growth. Since brain growth drives the bony plates apart at the sutures, a primary lack of brain growth allows premature fusion of all the sutures. Intracranial pressure usually is normal, and surgery seldom is needed. Typically, failure of brain growth results in microcephaly. Intrauterine space constraints may play a role in the premature fusion of sutures in the fetal skull. This has been demonstrated in coronal craniosynostosis.

Clinical Features

Craniosynostosis may be evident at birth or in infancy from craniofacial abnormalities. It is equally distributed in both genders. It may become evident later when the child exhibits neurodevelopmental delays. Typically, careful examination alone can make the diagnosis. Craniosynostosis sometimes is associated with sporadic craniofacial syndromes such as Crouzon, Apert, Chotzen, Pfeiffer, or Carpenter syndromes. In this context, facial features, typically craniofacial abnormalities, suture ridging, and early closure of fontanels, suggest the diagnosis. Raised intracranial pressure is rare with fusion of a single suture. Intracranial pressure may be elevated in primary multiple suture craniosynostosis, such as cloverleaf skull and the syndromic synostoses. Signs include sun-setting eyes, papilledema, vomiting, and lethargy. Differential diagnoses include benign skull tumors, hydrocephalus, mental retardation, neural tube defects, syringomyelia, thyroid disease and torticollis.

Radiographic Features

Skull X-ray with anteroposterior, lateral, and Waters’ views show prematurely fused sutures which are easily identified by the absence of sutures and associated ridging of the suture line. Sutures either are not visible or have evidence of sclerosis.

Treatment and Prognosis

In the past 30 years, a better understanding of the pathophysiology and management of craniosynostosis has developed. Currently, surgery is usually cosmetic for infants with fusion of one or two sutures that result in a misshapen head. For infants with microcephaly (i.e. secondary craniosynostosis), surgery usually is not required. Surgery typically is indicated for increased intracranial pressure or for cosmetic reasons. Patients with primary craniosynostosis must be monitored after surgery. In secondary craniosynostosis, prognosis is dependent upon underlying etiology.

Clinical Features

Although there is considerable individual variation in the appearance of patients with craniofacial dysostosis, the signs are all basically due to early synostosis of the sutures. Facial deformity is observed at birth, followed — with time — by other features of the syndrome. Coronal and sagittal sutures are obliterated; fontanels remain not obliterated and pulsating for a long time. Lateral and anteroposterior flattening of the acrocranium is observed, growing only at the vertical axis. Anteroposterior diameter is smaller than transverse diameter. The forehead is high and wide. Wide face and hypoplastic maxilla producing pseudoprognathism are observed. Deviation of the nasal septum, narrowed or obliterated anterior nares, and wide beaked nose are present. Hypertelorism, divergent squint, eyelid seems antimongoloid, and upper eyelid mimicking ‘frog face’ are observed. The upper lip is shortened and sometimes cleaved. Progressing optic nerve atrophy leads to vision impairment because of the intracranial hypertension. Impairment of hearing indicates disorders of the middle ear. Malocclusion, malposed teeth, and dysphasia are noted. Short stature and no physiologic spinal curvature are observed. The skin usually is dark. Syndromic acanthosis nigricans appears in the axillary fossa, the angle of the mouth, and on the lips in children. Patients report headache. Convulsions often occur; mental retardation is frequently observed (Fig. 17-15).

Radiographic Features

Skull, spine, and hand radiography is usually necessary to confirm the diagnosis. Skull radiography reveals the following: obliterated sutures (mostly coronal, sagittal); shallow eye sockets (exophthalmos); shortened anterior cranial fossa; underdeveloped lateral nasal sinuses; tympanic membranes fixed obliquely, narrowed external auditory canals, and small pyramids with symptoms of sclerosis; On spine radiography, the presence of bifid spinous process is possible, and slight symptoms of achondroplasia may be visible. Radiographic examination of the metacarpal bones and fingers reveals slight achondroplasia.

Treatment and Prognosis

A neurosurgical procedure is recommended in cases of intracranial hypertension leading to further optic atrophy. The surgery is difficult, and the procedure must be considered and undertaken in stages. Plastic surgery of the face could be of great help. It is one of the few syndromes where the cosmetic results of the surgery can be strikingly effective. These patients may ultimately come to lead a relatively normal life.

Clinical Features

Wide variations in the clinical expression of this syndrome are recognized, ranging from a complete, typical form manifesting all abnormalities listed below through incomplete, abortive, and atypical forms. The important clinical manifestations of the disease are:

The characteristic faces of the patients have often been described as being bird like or fish like in nature.

The syndrome is thought to result from a retardation or failure of differentiation of maxillary mesoderm at and after the 50 mm stage of the embryo. The fact that the teeth of the upper jaw are usually unaffected, and ordinarily are present by the sixth week, is further evidence of retardation or arrest of differentiation at or after the second month of fetal life. The first visceral arch of the visceral mesoderm also advances secondarily to form the mandible, and again retardation occurs on the same basis.

A disease that has sometimes been confused with mandibulofacial dysostosis because of certain clinical features in common is hemifacial microsomia (also known as oculoauriculovertebral dysplasia or Goldenhar syndrome). However, hemifacial microsomia is sporadic in the vast majority of cases, although familial cases have been reported. In addition as the name implies, this disease is unilateral and has been suggested to be related to an abnormality in the vascular supply of the head. It has been discussed in detail by Gorlin and his associates.

Radiographic Features

As Pavsek pointed out, the bodies of both malar bones tend to be grossly and symmetrically underdeveloped in mandibulofacial dysostosis. There may be agenesis of the malar bones with nonfusion of the zygomatic arches, as well as absence of the palatine bones. Cleft palate may be visible on the radiograph. There is usually hypogenesis, and sometimes agenesis of the mandible. The paranasal sinuses are grossly underdeveloped. The auditory ossicles are often absent, and the cochlea and vestibular apparatus may be deficient. The cranial vault is normal in most instances.

Treatment and Prognosis

There is no treatment for this condition, but the prognosis is good, most patients living a normal life span.

Etiology

Three pathophysiological theories exist to explain the occurrence of Pierre Robin sequence:

Clinical Features

This heterogeneous birth defect has a prevalence of approximately 1 per 8,500 live births. The maleto-female ratio is 1:1. Micrognathia is reported in the majority of cases (91.7%). The mandible has a small body, obtuse gonial angle, and a posteriorly located condyle. The mandibular hypoplasia; however, resolves and the child attains a normal profile by the age of five to six years. Glossoptosis is noted in 70–85% of reported cases. Macroglossia and ankyloglossia are relatively rare findings, noted in 10–15% of reported cases. The combination of micrognathia and glossoptosis may cause severe respiratory and feeding difficulty in the newborn. Obstructive sleep apnea may also occur. The prevalence of cleft palate varies from 14–91%. It can affect the soft and hard palate and is usually U-shaped (80%) or V-shaped (Fig. 17-17). Occasionally, it may present as a bifid or double uvula or as an occult submucous cleft. Velopharyngeal insufficiency is usually more pronounced in these patients than in those with isolated cleft palate.

Other associated anomalies are also seen which include; otitis media, hearing loss, nasal deformities, dental and philtral malformations. Anomalies involving the musculoskeletal system are the most frequent systemic anomalies (noted in 70–80% of cases). They include syndactyly, dysplastic phalanges, polydactyly, clinodactyly, hyperextensible joints, and oligodactyly in the upper limbs. Central nervous system (CNS) defects such as language delay, epilepsy, neurodevelopmental delay, hypotonia, and hydrocephalus may occur.

Treatment and Prognosis

A multidisciplinary approach is required to manage the complex features involved in the case of these children. Treatment is prioritized according to the severity of airway compromise followed by the extent of feeding difficulties. Infants with pronounced micrognathia may experience severe respiratory distress or failure to thrive. Surgical intervention is necessary in these cases.

Etiology

More than 98% of cases of Apert syndrome are caused by specific missense substitution mutations (i.e. Ser252Trp, Ser252Phe, Pro253Arg) involving fibroblast growth factor receptor 2 (FGFR2), which maps to chromosome bands 10q25–q26. The remaining cases are due to mutations in or near exon 9 of FGFR2. Fibroblast growth factor receptor 2 (FGFR2) mutations lead to an increase in the number of precursor cells that enter the osteogenic pathway. Ultimately, this leads to increased subperiosteal bone matrix formation and premature calvaria ossification during fetal development. The order and rate of suture fusion determine the degree of deformity and disability. The evidence that syndactyly of Apert syndrome could be a keratinocyte growth factor receptor (KGFR)-mediated effect has also been reported.

Clinical Features

Apert syndrome is detected in the neonatal period due to craniosynostosis and associated findings of syndactyly in the hands and feet. Asians have the highest reported prevalence (22.3 per million live births). No gender predilection is seen. Craniostenosis is present and most commonly involves the coronal sutures, resulting in acrocephaly, brachycephaly, flat occiput, and high prominent forehead. Large late-closing fontanels and a gaping midline defect are seen. Patients have apparent low-set ears with occasional conductive hearing loss. Eyes exhibit down-slanting palpebral fissures, hypertelorism, shallow orbits, proptosis and exophthalmos. The nose has a markedly depressed nasal bridge. It is short and wide with a bulbous tip, parrot-beaked appearance, and choanal stenosis or atresia (Fig. 17-18A, B).

The jaw shows a prominent mandible, maxillary hypoplasia, drooping angles of the mouth, high arched palate, bifid uvula, cleft palate, crowded upper teeth, malocclusion, delayed and ectopic eruption, shovel-shaped incisors, supernumerary teeth, V-shaped maxillary dental arch, and bulging alveolar ridges.

Syndactyly involves the hands and feet with partial-tocomplete fusion of the digits, often involving second, third, and fourth digits. These often are termed mitten hands and sock feet (Fig. 17-19). In severe cases, all digits are fused, with the palm deeply concave and cup-shaped and the sole supinated (Fig. 17-20). Intelligence varies from normal to subnormal mentality. Malformations of the CNS may be responsible for most cases. Papilledema and optic atrophy with loss of vision may be present in cases of subtle increased intracranial pressure. Hyperhidrosis is commonly seen. Cardiovascular manifestations like atrial septal defect, patent ductus arteriosus, ventricular septal defect and pulmonary stenosis are present. Gastrointestinal, genitourinary and respiratory symptoms may be present in a small percentage of cases.

Treatment

Surgical care involves early release of the coronal suture and fronto-orbital advancement and reshaping. Prognosis largely depends on the age at operation. Craniosynostosis can result in brain compression and mental retardation unless relieved by early craniotomy.

Clinical Features

A macrocephalic head with a frontal bossing, a flattened nasal bridge, and proptotic eyes has been observed. In TD2, a cloverleaf-shaped skull resulting from premature closure of the cranial sutures. Narrow thorax with small ribs, micromelic limbs with brachydactyly, protuberant abdomen, hydrocephalus and other cerebral parenchymal abnormalities are seen. Characteristic orodental abnormalities are not described associated with this syndrome.

Prognosis

TD is usually lethal in the first few days of life. Death is caused by respiratory insufficiency.

Etiology

Achondroplasia is caused by mutations in the gene for fibroblast growth factor receptor-3 (FGFR3). The gene has been mapped to band 4p16.3. The common mutations cause a gain of function of the FGFR3 gene, resulting in decreased endochondral ossification, inhibited proliferation of chondrocytes in growth plate cartilage, decreased cellular hypertrophy, and decreased cartilage matrix production.

Clinical Features

Frequency is believed to be 1 case per 15,000–40,000 births worldwide (Fig. 17-21). Cardinal features include short stature, rhizomelic shortening of the arms and legs, a disproportionately long trunk, trident hands, midfacial hypoplasia, prominent forehead (frontal bossing), thoracolumbar protuberance, true megalencephaly, and characteristic limitation of joint motion. The incongruous appearance of the achondroplastic dwarf is in contrast to that of the pituitary dwarf, and the incongruity becomes more pronounced as he/she approaches adulthood and later life, chiefly because of the disproportionate size of the head in relation to the remainder of the body. Despite their misshapen appearance, achondroplastic dwarfs are of normal intelligence. Often they are also endowed with unusual strength and agility, characteristics which have led some to adopt the occupation of professional wrestler.

Oral Manifestations

The maxilla is often retruded because of restriction of growth of the base of the skull, and the retrusion may produce a relative mandibular prognathism (Fig. 17-22). The resultant disparity in size of the two jaws produces an obvious malocclusion. The dentition itself is usually normal, although congenitally missing teeth with disturbance in the shape of those present have been reported.

Radiographic Features

Radiographs of the skull, spine, and extremities reveal the characteristic features. A lateral skull radiograph demonstrates midface hypoplasia, enlarged calvaria, frontal prominence, and shortening of the base of the skull. The size of the foramen magnum is diminished. The long bones are shorter than normal, and there is thickening or mild clubbing of the ends. The epiphyses generally appear normal, but may close either early or late. The bones at the base of the skull fuse prematurely. Except for the retrusion of the maxilla and the malocclusion between the two jaws, there are no changes in the jawbones.

Histologic Features

The abnormality seen in the bone of patients with achondroplasia is failure of endochondral ossification. Intramembranous and periosteal ossification are undisturbed. Histologic studies have shown disarray of the chondrocytes, with loss of columnation and loss of normal chondrocyte proliferation. Fibrous tissue is present in the zone of provisional calcification, but bone trabeculae present are irregular. Because endochondral growth is affected, the orderly longitudinal growth of bone is disrupted, resulting in stunting of the bone. Intramembranous ossification is normal, leading to normal clavicles and skull. Because the width of the long bones is a product of intramembranous periosteal ossification, these bones are of normal diameter.

Treatment and Prognosis

There is no treatment for achondroplasia. There may be delay in motor milestones but speech is normal. The frequent middle ear infections and dental crowding require attention. If the patient survives the first few years of life, the chances are excellent that he/she will have the life expectancy of a normal person.

Clinical Features

The features described refer to both types of this syndrome. The patients usually have most of these signs in varied proportions.

Complications

These include frequent ear infections and hearing loss, hypotonia, risk for developmental delays, breathing or respiratory problems, feeding difficulties, photophobia (light sensitivity) and esophageal reflux.

Clinical Features

The disease is usually not discovered until adult life, and in nearly all reported cases, has been a chance finding. The facial appearance of these patients may be altered and this may be the reason that they seek professional advice. Such a case has been reported by Dyson. The face may appear swollen, particularly with widening at the angles of the mandible and at the bridge of the nose. Some patients also have loss of visual acuity, loss of facial sensation, some degree of facial paralysis and deafness, all due to cranial nerve involvement through closure of foramina. Intraorally, there is sometimes overgrowth of the alveolar process. Most patients, except for the facial appearance, appear normal and are free of symptoms, including bone tenderness.

Radiographic Features

A skeletal survey will reveal increased density of many bones of the body, although some bones, such as those of the hands and feet, may be unaffected. The skull also exhibits diffuse sclerosis, as may the jaws.

Histologic Features

The bone is normal dense bone but without evidence of remodeling.

Differential Diagnosis

Three other diseases must also be considered in the diagnosis inasmuch as they may also present widespread sclerosis: osteopetrosis, osteitis deformans and progressive diaphyseal dysplasia.

Treatment and Prognosis

There is no treatment for the disease, although the patients usually lead a normal life.

Treatment

During infancy, cardiac surgery is often required to treat congenital malformations.

Clinical Features

Cleidocranial dysplasia is characterized by abnormalities of the skull, teeth, jaws and shoulder girdle as well as by occasional stunting of the long bones. In the skull the fontanels often remain open or at least exhibit delayed closing, and for this reason tend to be rather large. The sutures also may remain open and wormian bones are common. The sagittal suture is characteristically sunken, giving the skull a flat appearance. Frontal, parietal, and occipital bones are prominent and the paranasal sinuses are underdeveloped and narrow. Based on the cephalic index, the head is brachycephalic, or wide and short, with the transverse diameter of the skull being increased. A variety of other skull abnormalities are sometimes present. Additional abnormalities include calvarial thickening in the supraorbital part of the frontal bone, squamous part of the temporal bone and the occipital bone; occasional absence of the parietal bones, faulty development of the foramen magnum, and dysplasia of the paranasal sinuses. An excellent review and discussion of the varied clinical findings in cleidocranial dysplasia has been published by Kalliala and Taskinen.

The defect of the shoulder girdle, from which the condition derives a portion of its name, ranges from complete absence of clavicles, in about 10% of cases, to partial absence or even a simple thinning of one or both clavicles (Figs. 17-24 A, 17-25). Because of this clavicular disturbance, the patients have an unusual mobility of the shoulders and may be able to bring their shoulders forward until they meet in the midline (Fig. 17-24B). Defects of the vertebral column, pelvis and long bones, as well as bones of the digits, are also relatively common. Thus cleidocranial dysplasia, once thought to be a disease involving only membranous bones, is now recognized as affecting the entire skeleton. In addition, changes outside the skeleton, such as anomalous muscles, have been reported, but these may be secondary to the bony involvement.

Oral Manifestations

Patients with cleidocranial dysplasia characteristically exhibit a high, narrow, arched palate, and actual cleft palate appears to be common. The maxilla is almost invariably reported to be underdeveloped and smaller than normal in relation to the mandible. However, Davis has reported that in a series of patients studied by cephalometric analysis all showed that the maxilla was of normal size and the position was either normal or anteriorly positioned in all cases. In addition, 70% of the affected patients had larger mandibles than those of controls, which suggests that patients with cleidocranial dysplasia have enlarged mandibles rather than small maxillae, as reported in the literature. These findings remain to be confirmed. The lacrimal and zygomatic bones are also reported to be underdeveloped.

One of the outstanding oral findings is prolonged retention of the deciduous teeth and subsequent delay in eruption of the succedaneous teeth. Sometimes this delay in tooth eruption is permanent. The roots of the teeth are often somewhat short and thinner than usual and may be deformed.

In addition, Rushton reported that there is absence or paucity of cellular cementum on the roots of the permanent teeth, and this may be related to the failure of eruption so frequently seen. This has also been studied by Smith, who confirmed the absence of cellular cementum on both deciduous and permanent teeth. A surprising and unexplained feature was the absence of this cementum on the erupted teeth in both dentitions, with no increased thickening of the primary acellular cementum. The manner of anchorage of periodontal fibers and the maintenance of periodontal ligament width are also not understood in this disease. Furthermore, it is characteristic for numerous unerupted supernumerary teeth to be found by radiographic examination (Fig. 17-26). Crypt formation around impacted teeth, and ectopic teeth have been reported.

These are most prevalent in the mandibular premolar and incisor areas. Interestingly, partial anodontia has also been recorded in this condition but is rare.

Radiographic Examination

Reveals the widely patent anterior fontanel and sutures with wormian bones in cranium. The clavicles typically are reduced to single or double fragments on each side with middle part being deficient. Frequently the changes are asymmetric. Marked delay in ossification of pelvic bones especially pubic and ischial bones is regulary observed. Spina bifida occulta is observed in the cervical and upper thoracic levels. Hands and feet demonstrate various anomalies including shortening and broadening of carpal, metacarpal, tarsal, metatarsal bones.

Treatment and Prognosis

There is no specific treatment of cleidocranial dysplasia, although care of the oral conditions is important. The retained deciduous teeth should be restored if they become carious, since their extraction does not necessarily induce eruption of the permanent teeth. However, in recent years, there has been increasing use of a multidisciplinary approach to treatment of these patients, utilizing the pedodontist, the orthodontist, and the oral surgeon. It has been found, as in the case reviewed by Hutton and his associates, that the permanent teeth do have the potential to erupt and that correct timing of surgical procedures for uncovering teeth and orthodontic repositioning can give excellent functional results. Life expectancy is normal. Complications may arise during delivery in cases with narrow pelvis.

Clinical Features

Down syndrome is the most common autosomal abnormality and occurs in approximately 1 per 700 live births. Down syndrome accounts for the majority of mentally handicapped children in the preschool age category. It has been reported in people of all races. Both genders are affected equally. Characteristic morphologic features of mongolism can be recognized immediately at birth, but they are obvious in children older than one year. The major features of Down syndrome are mental retardation which can be mild to severe with an intelligence quotient (IQ) of 25–50; characteristic head appearance; small head (brachycephaly), flat facies with increased interocular distance (hypertelorism), depressed nasal bridge, flat occiput, and broad short neck. Narrow, upward and outward slanting of the palpebral fissures, medial epicanthal folds, strabismus, cataract and retinal detachment are the ocular anomalies. Small and misshapen ears with anomalies of the folds are observed. Skeletal anomalies include short stature; broad and short hands, feet, and digits; short curved fifth finger (dysplasia of the midphalanx), clinodactyly of the fifth finger; dysplasia of the pelvis; joint laxity; a wide gap between the first and second toes; and atlanto-occipital instability. Muscle hypotonia in newborns with decreased response to normal stimuli has been reported.

Protuberant abdomen (with or without an umbilical hernia), hypogenitalism, hypospadia, cryptorchism, and delayed and incomplete puberty. Congenital defects of the heart, or endocardial defects (40%), duodenal atresia, Hirschsprung disease, polydactylia, and syndactylia are reported. Other features include recurrent respiratory infections, leukemia (1%), epilepsy (10%), hypothyroidism (3%), and presenile dementia.

Oral Manifestations

Small mouth with protrusion of the tongue (macroglossia) with difficulty in eating and speaking, scrotal tongue, hypoplasia of the maxilla, delayed tooth eruption, partial anodontia, enamel hypoplasia, juvenile periodontitis, and cleft lip or palate (rare) are noticed commonly. Fissuring and thickening of the lips and angular cheilitis are frequent and gets increased in incidence and severity with age. Cheilitis occurs with greater frequency in children with Down syndrome than in unaffected persons. It is explained by mechanical factors, trauma, actinic influence, atopy, avitaminosis, or low-grade infections (candidiasis). A fissured tongue (plicated or scrotal) occurs in as many as 80% of children with Down syndrome, but it affects about 5% of the general population. Geographic tongue occurs in 11.3% of patients with Down syndrome. Juvenile periodontitis is a feature of Down syndrome, and its incidence among the various age groups parallels the occurrence of cheilitis but without significant correlation.

Treatment and Prognosis

No specific therapy exists for the congenital problems of patients with Down syndrome. About 25–30% of patients with Down syndrome die during the first year of life. The most frequent causes of death are respiratory infections (bronchopneumonia) and congenital heart disease.