Progeroid Short Stature With Pigmented Nevi
Description
Mulvihill-Smith syndrome is characterized by premature aging, multiple pigmented nevi, lack of facial subcutaneous fat, microcephaly, short stature, sensorineural hearing loss, and mental retardation. Immunodeficiency may also be a feature. Adult manifestations include the development of tumors, a sleep disorder with severe insomnia, and cognitive decline (summary by Yagihashi et al., 2009).
Clinical FeaturesShepard (1971) reported a case of low-birth-weight dwarfism with mild to moderate mental retardation, striking multiple pigmented nevi, and lack of facial subcutaneous fat, causing a somewhat bird-like face. Elliott (1975) gave further information on this patient, and Tynan and Zackai (1993) provided additional follow-up information: At the age of 25 years, he had developed esophageal ulceration following cyclical vomiting, and showed thoracic scoliosis, high-frequency deafness, some reduced joint mobility, and hypersensitivity to touch. The patient was retarded with an IQ less than 50. He had no speech. He was also found to have a bicuspid aortic valve with mild aortic stenosis.
Mulvihill and Smith (1975) reported a 17-year-old boy, born of unrelated parents, who had short stature of prenatal origin, features of premature aging, microcephaly, bird-like facies, multiple pigmented nevi, and mental deficiency. The pigmented nevi were noted at birth, with more appearing over time, and his growth parameters were always in the 3rd centile. He developed insulin-dependent diabetes at age 11 and had chronic bronchitis. Examination revealed short stature, microcephaly with a disproportionately small face, metopic bony prominence, prominent ears with absent ear lobes, and a notched tip to the nose. The mouth and mandible were small with several congenitally absent teeth and moderate malocclusion; individual teeth were ridged and hyperlucent. There was a moderate sensorineural hearing deficit bilaterally, and his voice was both high pitched and hoarse. He had a protuberant, relatively obese abdomen compared to the scant subcutaneous tissue of the upper trunk, widely spaced nipples, and small penis with first degree hypospadias. All joints had a limited range of motion that was about one-half of normal, and he had a broad-based shuffling gait. Neurologic examination showed agitation, impaired intellect, and hypersensitivity to touch. Blood counts were normal until age 17 years, when iron deficiency anemia was documented; he also had low IgG and borderline low IgA and IgM levels.
Baraitser et al. (1988) described a 7-year-old boy, born of unrelated parents, with intrauterine growth retardation, short stature, microcephaly, mild mental retardation, bird-like facies with lack of subcutaneous fat, small jaw, prominent ears with deficient lobules, sensorineural hearing loss, high 'piping' voice, and hypospadias. There were multiple pigmented nevi over the body, which had normal subcutaneous tissue. At age 6 years, he developed painless enlargement of the liver, associated with a modest rise in AST and ALT, but without jaundice; other hepatic parameters were normal, except for a slightly low IgG level. He had an unaffected sister.
Ohashi et al. (1993) suggested that the same disorder was present in a 30-year-old woman who had many of the features described in previously reported cases but who also had immunodeficiency. They suggested that immunodeficiency was a late development of the disorder. The patient had severe T-cell dysfunction and suffered from severe verruca vulgaris and a chronic, active Epstein-Barr virus infection. The fact that her parents were first cousins suggested autosomal recessive inheritance of the disorder, which they termed Mulvihill-Smith syndrome. Ohashi et al. (1993) referred to a case reported by Wong et al. (1979) that may represent the same disorder.
Bartsch et al. (1994) restudied and reinterpreted a patient previously reported by Tympner et al. (1978) as a new syndrome of 'progressive combined immunodeficiency and ectomesodermal dysplasia.' They showed that the disorder is identical to the Mulvihill-Smith syndrome, a progeroid disorder. The patient suffered from severe viral infections, allergic rhinitis and conjunctivitis, delayed puberty, visual loss, modest achievement in high school, and reactive depression. His intelligence was normal but lower than that of his parents. Pigmented nevi appeared at the age of approximately 1 year. He had short stature (height = 160.2 cm) and had received growth hormone treatment between ages 13 to 16 years. By the age of 20 years, he had required a right corneal transplant for a perforated ulcer. Bartsch et al. (1999) provided follow-up on the patient originally reported by Tympner et al. (1978). He developed hearing loss requiring a hearing aid, bilateral cataracts with near-blindness by the time of his death, loss of mobility of knee joints resulting in walking disability, and panic attacks. At 23.3 years of age, he underwent neurologic evaluation for progressive locomotor ataxia over the previous 6 months; cranial CT scan revealed cerebral tumor metastases, which were found to be secondary to gastric carcinoma, with metastases in the liver and peritoneum as well. He died at 23.5 years of age; no autopsy was performed.
De Silva et al. (1997) reported the seventh case of the Mulvihill-Smith progeria-like syndrome in a 5-year-old boy with a thin, pinched face, failure to thrive, and cutaneous pigmented nevi. The patient's motor and intellectual development were normal. He showed lymphopenia, low IgG2 and IgG4 immunoglobulins, and an absent in vitro proliferative response to pokeweed mitogen. Chromosomal mitomycin and radiation sensitivity was normal. Skin fibroblast growth in culture was slow, and the fibroblasts appeared morphologically different from normal controls in their size and large number of inclusions.
Ferri et al. (2005) examined a 25-year-old woman, born of nonconsanguineous parents, who had a senile appearance, short stature, microcephaly, peculiar facies with scarce subcutaneous adipose tissue in the lower part of the face with atrophic-appearing skin, deep-set eyes, narrow nasal bridge, retrognathia, sensorineural hearing impairment, high-pitched voice, diffuse pigmented skin lesions primarily on the trunk, and microcytic anemia with immunologic abnormalities, including decreased levels of IgG, IgA, and gamma globulins. At 22 years of age, she underwent surgical removal of a squamous cell carcinoma from the left side of her tongue. Menopause occurred at 24 years of age. At age 25, she had bilateral hypermetropic astigmatism, amyotrophic amblyopia, and posterior cortical cataract. Neurologic examination showed that she was not well oriented to time and had a slightly ataxic gait and fine postural tremor of both hands. MRI showed only mild enlargement of cortical sulci. Evaluation for excessive daytime sleepiness and severe nocturnal insomnia with nighttime movement disorder indicated a sleep disruption consistent with agrypnia excitata (see 600072). Ferri et al. (2005) noted that the patient's condition deteriorated progressively with daytime fluctuations of confusion and alertness with visual hallucinations, and she died at 26 years of age.
Yagihashi et al. (2009) described a 28-year-old Japanese woman, born of normal unrelated parents, with Mulvihill-Smith syndrome who developed tumors, a severe sleep disorder, and cognitive decline. She had a solid pseudopapillary cystic tumor of the pancreas removed at 17 years of age; at 25 years of age, an incidental cerebellar mass was identified on MRI that remained unchanged 3 years later and was considered to be a benign tumor or cyst. In addition, a tongue tumor was removed at 27 years of age, which was revealed to be an ulcer with chronic inflammation by histopathology. At age 20 years, she developed diabetes mellitus treated with oral hypoglycemics. At age 24, band keratopathy and cataract developed, and she underwent bilateral corneal transplantations followed by intraocular lens placement. At age 26, she developed a sleep disturbance involving severe insomnia with disappearance of sleep spindles and K-complexes, persisting muscle tone, and loss of slow-wave sleep. Clinical and neurophysiologic studies were compatible with agrypnia excitata, a sleep disorder attributable to dysfunction of the thalamo-limbic system. Brain MRI and SPECT imaging revealed structural and functional deficits in the dorsomedial region of the thalamus. The patient also had rapid and severe decline in acquired cognitive function, with distinct cognitive impairments resembling dementia, including intellectual deficits, memory disorder, and executive dysfunction. Citing the 2 previously reported adult patients with Mulvihill-Smith syndrome and tumors (Bartsch et al., 1999; Ferri et al., 2005), 1 of whom also exhibited sleep disorder and cognitive decline, Yagihashi et al. (2009) suggested that these features are adult manifestations of Mulvihill-Smith syndrome.
InheritanceBased on reports of both male and female patients with Mulvihill-Smith syndrome and the report of the syndrome in a consanguineous family by Ohashi et al. (1993), Yagihashi et al. (2009) suggested autosomal recessive inheritance of the disorder.