Osteopetrosis: Autosomal Recessive—Lethal (Infantile Malignant Osteopetrosis)
Dense, Thick, Fragile Bone; Secondary Pancytopenia; Cranial Nerve Compression
More than 100 cases of this genetically heterogeneous and commonly lethal group of disorders have been reported since the first cases were described. Two different subsets of patients are recognized based on bone morphology: (1) osteoclast-rich, associated with a high number of mature but nonfunctional osteoclasts; and (2) osteoclast-poor, in which these cells are absent because of a defect in differentiation. In both cases there is absence of proper bone resorption and an increased bone mass. It is estimated to occur in 1 of 250,000 births. Several genotypes of autosomal recessive osteopetrosis (ARO) have specific natural histories.
Growth. Normal birth parameters with subsequent failure to thrive and progressive macrocephaly. Short stature in untreated survivors.
Performance. Seizures secondary to hypocalcemia, blindness, hearing loss, intellectual disability (depends on genotype).
Craniofacial. Frontal bossing; open fontanel; progressive proptosis; strabismus; choanal stenosis; facial palsy; a tendency for primary molars and permanent dentition to be distorted and for teeth to fail to erupt; poor periodontal attachment, allowing for exfoliation; early decay.
Imaging. Thick, dense, fragile bone with modeling alterations such as obtuse mandibular angle, partial aplasia of distal phalanges, straight femora, block-like “bone within a bone” metacarpals, obliteration of bone marrow space.
Metabolic. Serum calcium level may be low and serum phosphorus level elevated, increased alkaline phosphatase.
Other. Hepatosplenomegaly secondary to extramedullary hematopoiesis; immunodeficiency.
Marrow impingement leads to pancytopenia. Compression of cranial foramina may lead to deafness, blindness, vestibular nerve dysfunction, extraocular muscle paralysis, other cranial nerve palsies, and hydrocephalus. Fractures are common. Ocular involvement, occurring at a median age of 2 months, is the most common presenting sign followed by seizures from hypocalcemia. Failure to thrive secondary to airway compromise occurs. Without treatment, life expectancy rarely exceeds adolescence for most forms. Problems with dentition and dental infection may include recurrent mandibular osteomyelitis.
This disorder has primarily an autosomal recessive inheritance pattern.
TCIRG1 mutations account for 50% of cases and present with a classic phenotype and a predominantly hematologic presentation. Neurologic issues are the result of compression of neural foramina rather than primary brain involvement. Hematopoietic stem cell transplant (HSCT) is effective. Founder mutations in Costa Rica make this form of ARO more common in this population.
CLCN7 mutations account for 15% of cases. Patients who are homozygous or compound heterozygous have a classic hematologic presentation; however, this mutation may cause severe primary involvement of the nervous system, specifically the brain and retina, which may not be mitigated by HSCT. Long-term survival without HSCT has been reported. Heterozygous mutations in this gene cause a spectrum of anomalies from bone sclerosis, fractures, and dental abscesses to asymptomatic increased bone mass. This gene is responsible for Albers-Schönberg disease.
OSTM1 mutations account for 5% of cases and include ARO associated with a lysosomal storage disorder and a particularly poor prognosis owing to severe brain anomalies and seizures. This condition is analogous to the gray-lethal phenotype in mice. HSCT has not been recommended in these patients.
PLEKHM1 mutations are rare (<1%), but they produce an ARO phenotype associated with much milder bone disease such that affected individuals have not needed HSCT.
Carbonic anhydrase II-dependent ARO is distinguished by its association with renal tubular acidosis and cerebral calcifications. HSCT is a therapeutic option.
NEMO -dependent osteopetrosis is rare, X-linked, and distinguished by the occurrence of lymphedema, immunodeficiency, and anhidrotic ectodermal dysplasia in affected males. HSCT is a therapeutic option.
SNX10 mutations, thus far reported only in the Palestinian population, cause a classic ARO that is ameliorated by HSCT. Mutations in this gene result in small osteoclasts with reduced reabsorptive capacity.
TNFSF11 (RANKL ) encodes the main osteoclast-differentiating factor produced by osteoblasts and stromal cells. Homozygous mutations in this gene cause a classic phenotype that is not rescued by HSCT because RANKL is not produced by hematopoietic lineages. Mutations in this gene account for 5% of cases.
TNFRSF11A (RANK) encodes the receptor for RANKL. Mutations in this gene account for 5% of ARO cases. Affected individuals have a severe skeletal phenotype with a milder hematologic presentation. It is recommended that this group be considered for HSCT early on the basis of severe skeletal rather than hematologic involvement. Affected individuals may have severe, prolonged hypercalcemia following transplantation.
Albers-Schönberg H: Eine bisher nicht beschriebene Allgemeinekrankung des Skelettes im Röntgenbilde, Fortschr Geb Roentgenstrahlen Nuklearmed 11:261, 1907.
Gerritsen EJA, et al: Autosomal recessive osteopetrosis: Variability of findings at diagnosis and during the natural course, Pediatrics 93:247, 1994.
Cleiren E, et al: Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the (CLCN7) chloride channel gene, Hum Mol Genet 10:2861, 2001.
Villa A, et al: Infantile malignant, autosomal recessive osteopetrosis: The rich and the poor, Calcif Tissue Int 84:1, 2009.
Pangrazio A, et al: RANK-dependent autosomal recessive osteopetrosis: Characterization of five new cases with novel mutations, J Bone Min Res 27:342, 2012.
Lenz-Majewski Hyperostosis Syndrome
Dense, Thick Bone; Symphalangism; Cutis Laxa
Since 1974, when Lenz and Majewski first proposed this condition as a distinct syndrome, 19 sporadic cases have been reported. The features in infancy differ greatly from those in older childhood, leading to difficulties in early diagnosis.
Growth. Intrauterine growth retardation, postnatal short stature, eventual severe emaciation.
Performance. Moderate to severe intellectual disability.
Craniofacial. Disproportionately large cranium with broad and prominent forehead; late closure of large fontanels; hypertelorism with protuberant eyes; frequent choanal stenosis or atresia; nasolacrimal duct stenosis; dysplastic enamel; late eruption of deciduous and permanent teeth.
Skin. Cutis laxa in infancy; later, skin becomes hypotrophic and thin with prominent, subcutaneous veins, especially over the scalp, creating the appearance of premature aging; cutaneous syndactyly of the digits; absence of elastic fibers on skin biopsy; sparse hair in infancy.
Limbs. Syndactyly, brachydactyly, dorsiflexion of fingers, hyperextensible joints.
Imaging. Proximal symphalangism, delayed ossification of ulnar rays, short or absent middle phalanges; broad, thick ribs and clavicles; widespread cortical sclerosis and thickening of bone in diaphyses, calvarium, vertebrae, and skull base; shallow and distorted orbits; long, flared, and radiolucent metaphyses, osteopenic epiphyses, long-bone hyperostosis; kyphoscoliosis, delayed bone age.
Other. Cryptorchidism and inguinal hernia in boys.
Facial palsy; cleft palate; large, floppy ears; small tongue; micrognathia; cerebral atrophy; dysgenesis of corpus callosum; communicating hydrocephalus secondary to venous obstruction of the jugular foramen; flexion contractures at elbows and knees; craniovertebral junction stenosis; dislocated hips (one case); hypospadias/chordee; early death.
At birth cutis laxa, large fontanels, and syndactyly are the most prominent features. Progressive hyperostosis becomes evident only after the first 6 months of life, often leading to erroneous diagnosis in infancy. Choanal stenosis may cause respiratory insufficiency and repeated episodes of pneumonia. Later this problem may be aggravated by relative thoracic immobility caused by rib widening. Enlarged mandible can occur with advancing age. Progressive disability related to the skeletal dysplasia occurs with advancing age. Poor weight gain and slow growth persist even after resolution of infantile feeding difficulties. The original patient described by Lenz and Majewski was 30 years of age when last reported. She was 120 cm tall, spoke only a few words, and was ambulatory.
This disorder has an autosomal dominant mode of inheritance. Heterozygous mutations in the phosphatidylserine synthase 1 (PTDSS1) gene, which encodes phosphatidylserine synthase 1 (PSS), are responsible.
Kaye CI, Fischer DE, Esterly BE: Cutis laxa, skeletal anomalies and ambiguous genitalia, Am J Dis Child 127:115, 1974.
Lenz WD, Majewski FA: A generalized disorder of the connective tissues with progeria, choanal atresia, symphalangism, hypoplasia of dentine and craniodiaphyseal hyperostosis, Birth Defects 10(12):133, 1974.
Majewski F: Lenz-Majewski hyperostotic dwarfism: Reexamination of the original patient, Am J Med Genet 93:335, 2000.
Sousa SB, et al: Gain-of function mutations in phosphatidylserine synthase 1 (PTDSSI) gene cause Lenz-Majewski syndrome, Nature Genetics 46: 70, 2014.