Adult height is reduced in pycnodysostosis with observed values ranging from 135 to 160 cm in males and 117 to 152 cm in females. While short stature is unquestionably a principal feature of this skeletal dysplasia, the high prevalence of lower extremity fractures, the substantial percentage of cases reported from developing regions of the world where nutrition may not be optimal, and a possible role of growth hormone deficiency (see below) suggest that nongenetic factors are also relevant in determining height at maturity in affected individuals. Almost no serial height data are available from pycnodysostosis patients, but inspection of the growth curves derived from cross-sectional data suggests that growth velocity is subnormal. Birth length appears to be normal or nearly normal. There also is disproportion with relatively well conserved truncal length compared to leg length such that the upper/lower ratio is increased (Fig. 137-1).32
A 48-year-old man with pycnodysostosis. This patient has short stature with short limbs and brachydactyly, as well as some typical facial features including micrognathia, beaked nose, and prominent forehead.
The hands and feet are typically short and broad with short digits, particularly affecting the terminal phalanges, which show distal flaring (Fig. 137-2). The nails are often dystrophic.34 The limbs are short, and bowing of the legs may be observed due to previous fractures. The clavicles are typically hypoplastic at their acromial end. The spine also may be deformed with kyphosis, scoliosis, or increased lumbar lordosis.34
Hands and feet from four related patients with pycnodysostosis. Brachydactyly is present in all patients and splaying of the distal phalanges is most apparent in the oldest patient on the right. The phenotypic variability is also shown, as the hand of the third patient is nearly normal in appearance.
On roentgenographic examination, the most striking feature is the pervasive increase in bone density (Fig. 137-3).32,34 This finding is confirmed by quantitative computerized tomography of the trabecular bone of the lumbar spine showing values of 250 to 300 percent of normal-for-age values and dual-photon x-ray densitometry which reveals lumbar spinal densities of 140 to 160 percent and femoral neck densities of 105 to 170 percent of normal control values, respectively.35 The medullary canals are visualized in all patients, but are somewhat narrowed by the osteosclerosis, a radiologic feature which distinguishes this disorder from osteopetrosis in which the marrow space becomes obliterated.36 Widening of the distal portion of the femurs (Erlenmeyer-flask deformity) is variably present. The distal phalanges are notably hypoplastic, often disappearing at the ungual tufts. This feature has been termed acro-osteolysis, which might be a misnomer because evidence for a lytic process does not exist. Vertebral anomalies also have been noted occasionally, including coxa valga and incomplete segmentation at C1-C2 and at L5-S.32,34 Serial roentgenograms of one patient documented the loss of the horns of the hyoid bone during childhood.37
Roentgenograms of two patients with pycnodysostosis. A, Anterior-posterior view of the hands of an 82-year-old women. Brachydactyly is apparent as is acro-osteolysis affecting the therminal phalanges. This latter finding is variable with greater severity of the second than fourth fingers in this patient. B, Anterior-posterior view of the femurs and pelvis of 6-year-old girl. Generalized osteosclerosis with narrowing of the medullary space is apparent.
Blood chemistries, including alkaline phosphatase, serum calcium, and serum phosphorus as well as levels of the bone-related hormones (parathyroid hormone, osteocalcin, calcitonin) are normal.3,11-13,35,38,39
In patients with pycnodysostosis, the head tends to be large with frontal and occipital bulging (Fig. 137-1). The anterior and posterior fontanels are usually open beyond the appropriate age of closure. Failure of cranial suture fusion may be detected on palpation.34 Mild-to-moderate exophthalmos may be noted. The nose is often prominent and beak-like.4 The lower portion of the face often has a full appearance, but the chin is generally small with retrognathia. The ears are normal in shape and position.
Roentgenograms of the skull reveal the same osteosclerotic changes noted throughout the appendicular skeleton.34 The orbital rims and the base of the skull tend to be particularly dense.4,40 The skull is typically dolichocephalic with frontal and occipital bossing. Any and all of the cranial sutures may be open, and the anterior and posterior fontanels may be patent. Wormian bones are observed frequently. The paranasal sinuses are hypoplastic or absent and the mastoid air cells often fail to pneumatize. The facial bones, maxilla, and mandible are generally hypoplastic. The angle of the mandible is obliterated, an apparently invariant and pathognomonic sign of this disorder.4,34,40
Inspection of the mouth reveals a high-arched palate with a deep groove in nearly all patients.40 Macroglossia also has been noted in some patients, probably being relative to the small mandible in these patients.
Numerous quantitative and qualitative dental abnormalities are found in patients with pycnodysostosis, including retention of deciduous teeth, delayed eruption of permanent teeth, and hypodontia, which was found in a majority of patients.4,40 The teeth may be small (microdontia) and have enamel hypoplasia, hypercementosis, obliteration of the pulp chamber, and/or hypoplasia of the dental roots. The teeth are usually malpositioned and crowded due to the presence of small alveolar arches. Malocclusion with an anterior crossbite is often noted.40 Dental caries are frequently problematic, attributed to the difficulties in maintaining good dental hygiene when the teeth are overcrowded.
Patients are prone to pathologic fractures, most commonly of the long bones. Edelson and colleagues reviewed the orthopedic findings in 14 related patients, ranging in age from 1½ to 50 years.32 Among 11 patients greater than 4 years of age, evidence of fractures was found in one or both tibiae in all but one individual. Femoral fractures were evident in all five teenage and adult patients, tending to be more severe in the older adults. Bilateral subtrochanteric femoral fractures occurred sequentially in a 50-year-old woman, a striking finding because this type of fracture constituted only 5 percent of femoral neck fractures in a large series.41 A survey of the long bones of the upper extremities revealed humeral, radial, or ulnar fractures in three adult patients.32 These transverse stress fractures of the long bones of the upper and lower extremities healed, but tended not to obliterate the fracture lines, which is an abnormal finding.
Defects in the spine also are common in pycnodysostosis. Among eight related patients who were 9 years of age or older, lumbar spondylolysis was present in all, affecting L4 and L5 in six cases and L5 only in two.32 In a 1989 review of the pycnodysostosis literature, Currarino identified six cases of spondylolysis at L5, one at L4, and two at L4 and L5 (including a 4-month-old patient).42 At least one case of spondylolisthesis, Grade I at L5, has been observed.32 Spondylolysis also can be observed in the cervical spine, usually at C2.32,42 For example, a 2½-year-old boy presented with spondylolysis at C2 and C3 after minor trauma. A year later, after minimal orthopedic treatment secondary to poor compliance, the C3 lesion had healed but the C2 spondylolytic lesion remained with some mild cervical instability.32
A radiologic skeletal survey in 14 related patients identified several other fracture sites.32 These included a metatarsal stress fracture with nonunion, a calcaneal stress fracture, three clavicular fractures, and four scapular fractures, generally through the base of the coracoid process, with nonunion in all instances. Whether fracture healing is adequate in patients with pycnodysostosis is not clear. It appears that the majority of fractures will heal, but the risk of nonunion is increased.32,43 In addition, the persistence of radiolucent fracture lines and the minimal increase in uptake of technetium pyrophosphate at fracture sites during bone scans has been cited as evidence that fracture healing is reduced in pycnodysostosis.32
Osteomyelitis of the jaw is a complication of pycnodysostosis that has been reported in several individuals, nearly all adults, who presented with draining intra- or extraoral fistulae, pain, and facial swelling, often a few months after dental extractions.6,44,45 Dental caries and/or periodontal disease, perhaps secondary to the crowding of teeth frequently observed in pycnodysostosis, may predispose to these infections.44 The primary site of the osteomyelitis has been the mandible, although rare cases involving the maxilla alone or in combination with the mandible have been reported. Aggressive therapy is required to cure these infections and has included curettage, removal of sequestra, and intravenous antibiotics. Persistent or recurrent infections have occurred, often necessitating removal of portions of the necrotic, infected bone. There have been two mortalities associated with osteomyelitis of the jaw: a patient who had a sequestrectomy and died 5 days later of unknown causes6 and a noncompliant patient with maxillary osteomyelitis who returned with meningitis and deteriorated despite antibiotic therapy.45 Three cases of mandibular osteomyelitis occurred after fractures sustained during dental extractions.6 These pathologic fractures tend not to heal properly, forming pseudoarthroses that need to be stabilized. The proclivity toward osteomyelitis of the jaw is not believed to result from a fundamental immunologic deficit, but rather from the poor vascularization observed in osteosclerotic bone.44 Moreover, adult bones are less well-vascularized than those of children and the mandible is less well-vascularized than the maxilla, providing a rationale for the proclivity of the mandibular infections in adult patients.
The vast majority of patients have normal peripheral blood smears despite imaging studies and bone biopsies routinely demonstrating impingement on the marrow cavity. A small number of patients have had myelophthisis, presenting as microcytic anemia, thrombocytopenia, and hepatosplenomegaly.7– 11 Examination of the bone marrow in three such cases revealed hypoplasia with fibrosis.7,9,11 One young girl9 with signs of myelophthisis had an older brother who also was affected by the skeletal dysplasia but had a normal peripheral blood smear. Moreover, the myelophthisis in the girl resolved spontaneously (X. Rialland, personal communication), which suggests that stochastic or environmental factors may be responsible in part for the development of bone marrow failure in pycnodysostosis.
The upper airway tends to be anatomically narrow due to an abnormally elongated soft palate with low-lying uvula, glossoptosis, and retrognathia.46– 48 In several patients, upper airway obstruction has been clinically significant, resulting in obstructive sleep apnea, chronic CO2 retention, pulmonary hypertension, and right heart failure.47– 49 Adenoidal and/or tonsillar hyperplasia has not been a striking feature in these patients, although a 3-year-old girl with mild obstruction benefited from adenoidectomy.46 One patient with severe obstruction and right heart failure was treated surgically by shortening of the soft palate with subsequent resolution of the obstruction and complications.47
Growth Hormone Deficiency
Two reports describing five children and two adults12,13 and unpublished data from four children (F. Griegg, Mount Sinai School of Medicine, New York, NY; K. Araki, Kochi Medical School, Kochi, Japan; W. Riley, Driscoll Children's Hospital, Corpus Christi, Texas; personal communications) have revealed that growth hormone deficiency may accompany pycnodysostosis. In the most extensive study,12 three of four children and two adults with pycnodysostosis were shown to have low basal growth hormone levels and inadequate responses to provocative testing with clonidine and glucagon. Circulating IGF-I levels also were low. All patients had normal glucose tolerance, thyroid function, and serum cortisol levels. Computerized tomographic scans of the head revealed normal hypothalamic-pituitary regions except in one child, who had a partially empty sella with mild cortical atrophy. Two children, who were treated with growth hormone (15 U/m2 /week divided into daily subcutaneous doses), experienced significant acceleration in growth after 1 year. Bone age, which was delayed prior to therapy, did not accelerate. One patient13 was treated with growth hormone for 2 years and showed continued growth acceleration, increasing in height from −4.8 standard deviations prior to therapy to −4.4 and −3.8 after 1 and 2 years of therapy, respectively. While growth hormone therapy appears to accelerate linear growth in pycnodysostosis patients with growth hormone deficiency, no data are available to demonstrate that heights at maturity will be increased. In addition, there is no explanation for the growth hormone deficiency. Because the sella turcica appears to be normal in most patients and the remainder of the pituitary function is normal, either cathepsin K deficiency directly affects growth hormone metabolism or feedback to the hypothalamic-pituitary axis in these patients with inadequate bone resorption results in down-regulation of growth hormone production and secretion.