Lenz-Majewski Hyperostotic Dwarfism

A number sign (#) is used with this entry because Lenz-Majewski hyperostotic dwarfism (LMHD) is caused by heterozygous mutation in the PTDSS1 gene (612792) on chromosome 8q22.

Description

Lenz-Majewski hyperostotic dwarfism is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, distinct craniofacial and dental anomalies, loose skin, and distal limb anomalies, particularly brachydactyly and symphalangism. Patients have multiple radiographic abnormalities due to progressive generalized hyperostosis that affects the cranium, vertebrae, and diaphyses of tubular bones, leading to severe growth retardation (summary by Sousa et al., 2014).

Clinical Features

Four unrelated patients were reported with a similar syndrome (Braham, 1969; Macpherson, 1974; Lenz and Majewski, 1974; Kaye et al., 1974; Robinow et al., 1977). The features were multiple congenital anomalies (delayed closure of fontanels, proximal symphalangism, prominent cutaneous veins), mental retardation, and progressive skeletal sclerosis with severe growth retardation. The patients had a progeroid appearance. The dental enamel was dysplastic. Skin hypoplasia and joint laxity suggested a connective tissue disorder. The sporadic occurrence and a somewhat advanced paternal age were consistent with dominant mutation. Choanal atresia is one of the anomalies.

Gorlin and Whitley (1983) reported a patient whose photograph showed strikingly loose and wrinkled atrophic skin of the hands with short digits and partial syndactyly. Scalp veins were prominent through thin, wrinkled, and atrophic skin. Breathing was accompanied by nasal 'snorting' due to marked bilateral narrowing of the nasal choanae, and nasolacrimal duct obstruction was present. Erupting teeth showed defective enamel. Radiologic features included progressive sclerosis of the skull, facial bones, and vertebrae; broad clavicles and ribs; short or absent middle phalanges; diaphyseal undermodeling and midshaft cortical thickening; and retarded skeletal maturation.

Chrzanowska et al. (1989) described a 10-year-old son of young, healthy, unrelated parents who had progeroid appearance; bilateral symmetrical shortening of the fingers and metacarpals, most pronounced in rays IV and V with soft tissue webbing of those fingers; short toes; marked sclerosis of the cranial base with thickening of the calvaria; loose, thin skin with marked hyperlaxity; hyperostosis of the iliac wings; bilateral humeroradial synostosis; and 'beginning' proximal symphalangism of fingers II and III bilaterally.

Majewski (2000) reported follow-up on the original patient with Lenz-Majewski syndrome reported by Lenz and Majewski (1974). At age 2.5 years, the patient had an enlarged anterior fontanel, an open metopic suture, and marked hypertelorism. There was macrostomia, deep root of the nose, high palate, short, yellow, carious teeth, and progeroid appearance. She had a short neck, broad clavicles, increased venous pattern of the forehead and thorax, decreased subcutaneous fat of the abdomen, and lumbar kyphoscoliosis. The forearms were short with limited elbow extension. The hands showed marked brachydactyly, cutaneous syndactyly, stiff finger joints, and hyperconvex nails. At age 9.5 years, she spoke a few single words and was toilet trained. Radiologic examination showed hip dysplasia, hyperostosis of the skull, and synostosis of the fourth and fifth metacarpals. Menarche occurred at age 19 years. At age 30 years, she was 120 cm tall and severely mentally handicapped. She had large, prominent eyes, marked hypertelorism, and divergent strabismus. The lips and tongue were thick, teeth were short, and mandible was enlarged. She had normal breast development, sparse subcutaneous fat, scant pubic hair, and absent axillary hair. The skin was weak and atrophic, and there were prominent veins. There was massive thickening of the long tubular bones, proximal synostosis of all metacarpals, proximal symphalangism of the fingers, marked kyphoscoliosis, and rectangular fibular deviation of the big toes. Majewski (2000) concluded that the hyperostosis and generalized osteosclerosis are progressive in Lenz-Majewski syndrome.

Saraiva (2000) reported the seventh case of Lenz-Majewski hyperostotic dwarfism in a 4-year-old Portuguese girl. In addition to most of the recognized manifestations of the syndrome, she had dysgenesis of the corpus callosum, mainly hypoplasia of the splenium but also of the genu, and mild hemispheric white matter atrophy. Both parents and 2 older sisters were phenotypically normal.

Wattanasirichaigoon et al. (2004) reported a sporadic case of Lenz-Majewski syndrome with newly recognized manifestations including facial palsy, cleft palate, and hydrocephalus developing later in infancy. Increased intracranial pressure was identified and treated early to prevent neurologic morbidity.

Dateki et al. (2007) reported a 17-year-old Japanese boy with a mild form of Lenz-Majewski syndrome. As a child, he had prominent veins in the scalp and abdominal wall, and later had delayed eruption of permanent teeth and enamel dysplasia. He had cutis laxa, a progeroid facial appearance with prognathism, wrinkled skin, large ears, interdigital webbing, and mild mental retardation. Skeletal changes included calvarial hyperostosis, sclerosis of the skull base, an enlarged sclerotic mandible, broad clavicles and ribs, and diaphyseal undermodeling of the tubular bones. The patient was considered to have a mild variant of the disorder because he had normal height and muscular build and absence of brachymesophalangy with proximal symphalangism. The family history was unremarkable; at the boy's birth, his father was 30 years of age.

Sousa et al. (2014) reported 2 additional unrelated patients with this disorder, a male of Kurd-Turkish descent and a female of Czech descent. Both had short stature (-4 and -10 SD, respectively), microcephaly (-4 and -5 SD, respectively), and moderate to severe intellectual disability. Craniofacial features included delayed closure of the fontanels, broad and prominent forehead, hypertelorism, large ears, macrostomia, and prognathism. Dental enamel hypoplasia, macroglossia, and choanal atresia occurred in 1 patient each. Both had loose skin with prominent cutaneous veins, brachydactyly with short or absent middle phalanges, phalangeal synostosis, and cutaneous syndactyly. Radiographic abnormalities included progressive skull and vertebral sclerosis, diaphyseal hyperostosis and undermodeling, broad clavicle and ribs, and meta- or epiphyseal radiolucency. Brain imaging of the girl showed cortical atrophy, hydrocephalus, and pituitary hypoplasia. The boy had cryptorchidism. A review of reported cases did not indicate advanced paternal age.

Inheritance

All reported cases of Lenz-Majewski syndrome have occurred de novo (Sousa et al., 2014).

Population Genetics

Sousa et al. (2014) stated that only 10 'typical' cases of LMHD had been reported worldwide.

Molecular Genetics

In 5 unrelated patients with Lenz-Majewski hyperostotic dwarfism, Sousa et al. (2014) identified 3 different de novo heterozygous mutations in the PTDSS1 gene: Q353R (612792.0001) was found in the 3 patients previously reported by Saraiva (2000), Wattanasirichaigoon et al. (2004), and Chrzanowska et al. (1989), whereas P269S (612792.0002) and L265P (612792.0003) were found in 1 patient each. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in a private exome sequencing database or in public databases. Patient fibroblasts carrying each of the 3 mutations showed profoundly increased synthesis of phosphatidylserine, consistent with gain of function. Unlike control cells, PTDSS1 serine-exchange activity was resistant to inhibition by exogenous phosphatidylserine. However, patient cells did not have increased cellular levels of phosphatidylserine, phosphatidylethanolamine, or phosphatidylcholine, indicating tight cellular regulation of phospholipid homeostasis. Expression of the mutations in zebrafish embryos caused a variety of dose-dependent developmental defects in 6 to 40% of embryos 5 days after fertilization. Defects included craniofacial anomalies, trunk angulation, small or absent eyes, and abnormal cartilage. A disturbance in normal apoptosis was not observed in mutant zebrafish. Skin fibroblasts from 2 patients showed cytoplasmic vacuolization possibly containing a storage material, but lipid accumulation was not different from controls. Sousa et al. (2014) noted that phosphatidylserine participates in intracellular signaling and appears to play a role in brain development as well as bone mineralization, suggesting that disrupted phosphatidylserine metabolism likely accounts for the clinical manifestations of LMHD.