Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 1003431005; ORPHA: 2457, 90153; DO: 0081128;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q22 | Mandibuloacral dysplasia | 248370 | Autosomal recessive | 3 | LMNA | 150330 |
A number sign (#) is used with this entry because of evidence that mandibuloacral dysplasia type A (MADA) with partial lipodystrophy is caused by homozygous or compound heterozygous mutation in the gene encoding lamin A/C (LMNA; 150330) on chromosome 1q22.
Atypical forms of MADA are also caused by mutation in the LMNA gene.
Mandibuloacral dysplasia with type A lipodystrophy (MADA) is an autosomal recessive disorder characterized by growth retardation, craniofacial anomalies with mandibular hypoplasia, skeletal abnormalities with progressive osteolysis of the distal phalanges and clavicles, and pigmentary skin changes. The lipodystrophy is characterized by a marked acral loss of fatty tissue with normal or increased fatty tissue in the neck and trunk. Some patients may show progeroid features. Metabolic complications can arise due to insulin resistance and diabetes (Young et al., 1971; Simha and Garg, 2002; summary by Garavelli et al., 2009).
See also MAD type B (MADB; 608612), which is caused by mutation in the ZMPSTE24 gene (606480).
Young et al. (1971) described 2 teenaged males with a hypoplastic mandible producing severe dental crowding, acroosteolysis, stiff joints, atrophy of the skin over hands and feet, and hypoplastic clavicles. The boys had an 'Andy Gump' appearance. Persistently wide cranial sutures and multiple wormian bones were noted. Alopecia and short stature were other features of this progeria-like syndrome.
Danks et al. (1974) suggested that the patient reported by Cavallazzi et al. (1960) may have had this disorder. The authors also suggested that the same disorder was present in the patient reported by McKusick (1963) as cleidocranial dysostosis with acroosteolysis and McKusick (1964) as pycnodysostosis. That patient died young. The differential diagnosis also includes Hajdu-Cheney syndrome (102500) and acrogeria (201200). Welsh (1975) reported a 'new progeroid syndrome' in 2 males and 2 females from a sibship of 14, suggesting autosomal recessive inheritance; this disorder may have been mandibuloacral dysplasia.
Pallotta and Morgese (1984) reported 2 Italian brothers with mandibuloacral dysplasia. Hall and Mier (1985) described a 13-year-old male with this disorder, and referred to 3 unpublished cases that included a 37-year-old male and a brother and sister. Tenconi et al. (1986) described an Italian family with 1 female and 2 males affected in a sibship of 11. They noted that of 9 reported affected families, 5 were Italian.
The 2 brothers reported by Parkash et al. (1990) as examples of Hutchinson-Gilford progeria syndrome (HGPS; 176670) probably had MAD (McKusick, 1991; Toriello, 1991; Cusano and Scarano, 1991). Parkash et al. (1990) commented that the patients had 2 unusual findings, namely, marked resorption of the mandible with loss of teeth in the elder sib and prolonged survival. At the time of report, both sibs were alive and active at ages 32 and 24 years. Both had hypoplastic clavicles with ease of apposition of the shoulders. Acroosteolysis with progressive loss of bone from the distal phalanges of the fingers and toes was found bilaterally. The cranial bones were thin and the anterior fontanels and sutures were still open. In the case of the youngest sib, wormian bones were also present. Parkash (1991) defended the diagnosis of progeria.
Cutler et al. (1991) and Freidenberg et al. (1992) emphasized the partial lipodystrophy present in the patients they observed. Cutler et al. (1991) described 2 patients with extreme insulin resistance and marked hypermetabolism. Freidenberg et al. (1992) studied the same 2 patients and a third patient, a 41-year-old male, who had been published as an instance of Werner syndrome (277700) at age 24 years (Cohen et al., 1973). Hearing loss was present in all 3 patients. In the patient with MAD syndrome who had previously been misdiagnosed as having Werner syndrome by Cohen et al. (1973), Ng and Stratakis (2000) found premature adrenal cortical dysfunction of the zona reticularis, marked by a decrease in 17,20-lyase activity (609300), consistent with that seen in the elderly. They suggested that the prominence of the patient's eyes was pseudo-proptosis, secondary to lack of subcutaneous periorbital fat.
Toriello (1995) reviewed published cases and examined the possibility of heterogeneity.
Seftel et al. (1996) reported a male newborn from South Africa (non-Italian descent) with confluent fontanels, sparse hair and eyebrows, severe micrognathia, bulbar digits, and short clavicles. These manifestations were consistent with mandibuloacral dysplasia. He also had glanular hypospadias and died at 8 days of age. Seftel et al. (1996) considered this case to represent a lethal neonatal form of the disorder.
Prasad et al. (1998) reported 2 brothers and 2 unrelated girls with typical features of MAD. Both girls presented with foot pain and had a small infantile uterus and soft tissue calcinosis.
Tudisco et al. (2000) stated that only 11 families of mandibuloacral dysplasia had been reported and that 5 of these were Italian. They described an additional Italian patient born of consanguineous parents. Consanguinity had previously been proved only in the family reported by Zina et al. (1981). In the 33-year-old patient of Tudisco et al. (2000), growth retardation, clavicular dysplasia, and delayed cranial suture closure were first noted at the age of 5 years, when a diagnosis of cleidocranial dysostosis was suggested. After the age of 18 years, alopecia, marked micrognathia, distal phalangeal shortening, and joint stiffness became apparent. His height was 161 cm, and he showed premature loss of the lower teeth. X-rays showed marked osteolysis of the distal finger phalanges, as well as delayed closure of cranial sutures, and mandibular and clavicular hypoplasia.
Simha and Garg (2002) studied body fat distribution in 2 male and 2 female patients with MAD by anthropometry, dual energy x-ray absorptiometry, and magnetic resonance imaging. Blood glucose and insulin responses during an oral glucose tolerance test and fasting serum lipoproteins were determined. Three of the 4 subjects had loss of subcutaneous fat from the extremities with normal or slight excess in the neck and truncal regions (termed type A pattern). In contrast, 1 patient had generalized loss of subcutaneous fat involving the face, trunk, and extremities (type B pattern; 608612). All of the patients had normal glucose tolerance but had fasting and postprandial hyperinsulinemia suggestive of insulin resistance. Elevated serum triglycerides with low high-density lipoprotein cholesterol levels were noted in 3 subjects. The authors concluded that MAD presents with 2 types of body fat distribution patterns, both of which are associated with insulin resistance and its metabolic complications.
Cogulu et al. (2003) described a 13-year-old girl with mandibuloacral dysplasia who had absent breast development, although pubic and axillary hair were normal. Menarche began at 10 years and she had regular menstrual cycles. Hormone studies revealed no abnormalities.
Afifi and El-Bassyouni (2005) reported 2 unrelated Egyptian girls with MAD, who were both born of consanguineous parents. Both patients had micrognathia, prominent eyes, pointed nose, high-arched palate, hypoplastic teeth, and sparse scalp hair. Other common features included loss of subcutaneous fat from both upper and lower limbs and hypo- and hyperpigmented spots over the trunk. Radiologic features showed delayed closure of the cranial sutures, micrognathia, and hypoplastic clavicles. The first patient also had acroosteolysis of the distal phalanges. Both patients had laboratory findings consistent with insulin resistance. Afifi and El-Bassyouni (2005) discussed the differential diagnosis of MAD and noted the phenotypic overlap with several disorders, including HGPS, Werner syndrome, Gottron type acrogeria, Hallermann-Streiff syndrome (234100), and Hajdu-Cheney syndrome.
Lombardi et al. (2007) identified a patient with an apparent MADA phenotype without clavicular hypoplasia, metabolic imbalances, and resembling limb-girdle myopathy. Clinical features included a hypoplastic mandible, acroosteolysis, pointed nose, partial loss of subcutaneous fat, and a progeric appearance. Due to the absence of clavicular dysplasia and normal metabolic profiles, generally associated with muscle hyposthenia and generalized hypotonia, the authors considered this phenotype an atypical laminopathy. The patient's cells showed nuclear shape abnormalities, accumulation of prelamin A, and irregular lamina thickness.
Kosho et al. (2007) reported a 56-year-old Japanese woman, born of consanguineous parents, with MAD and type A lipodystrophy confirmed by genetic analysis (150330.0046). The authors stated that she was the oldest reported patient with the disorder. In addition to the MADA phenotype, including progeroid appearance, acroosteolysis of the distal phalanges, and loss of subcutaneous fat in the limbs, she had severe progressive destructive skeletal and osteoporotic changes. Vertebral collapse led to paralysis. However, Kosho et al. (2007) also noted that other factors may have contributed to the severe osteoporosis observed in this patient.
Garavelli et al. (2009) reported 2 unrelated patients with early childhood onset of MADA features. The first child, a boy, presented at age 5 years, 3 months with bulbous distal phalanges of fingers. He was observed to have ocular proptosis, a thin nose, prominent cheeks, slight micrognathia, malocclusion with overlapping teeth, thin skin with prominent veins, skin spots, and lipodystrophy type A, with an acral loss of fatty tissue also evident on the shoulders. He had wormian bones, acroosteolysis, and decreased vertebral bone density. The second child was a girl, born of consanguineous parents from Pakistan. She presented at age 4 years, 2 months with a round face, chubby cheeks, thin nose, short, broad distal phalanges, and lipodystrophy type A, with subcutaneous fat more evident on the trunk than on limbs. Skeletal survey showed wormian bones, thin clavicles, and short terminal phalanges with acroosteolysis. Both patients were homozygous for the common R527H mutation in LMNA (150330.0021). Garavelli et al. (2009) emphasized that features of this disorder may become apparent as early as preschool age and that bulbous fingertips may be a clue to the diagnosis.
Guglielmi et al. (2010) provided follow-up on a 43-year-old man, whom they stated was the second oldest reported MADA patient, who had previously been studied by Novelli et al. (2002) and found to be homozygous for an R527H mutation (150330.0021) in the LMNA gene. The patient developed, over a period of nearly 2 years, deformation and swelling of the right elbow, associated with pain and nearly total loss of joint function, with elbow stiffness in slight flexion and severely limited articular excursion in both active and passive pronation and extension. Radiography of upper and lower limbs showed osteolysis and destructive processes of the right elbow, as well as asymptomatic resorption of both femoral greater trochanters that was more pronounced on the left. In particular, the right elbow showed joint space narrowing with loss of articular cartilage, dysplasia of the humeral condyles, erosion of proximal ulna and radius bilaterally, and palmar angulation of the ulnar olecranon with marked signs of hyperostosis and loss of normal articular contacts. Guglielmi et al. (2010) noted that these lesions were absent in radiographs from 7 years earlier, and only minor alterations were detectable in radiographs at onset of symptoms 3 years previously, including less extensive hyperostosis and condylar dysplasia, with preserved articular contacts and no palmar angulation of the ulna. In addition, progression of bone deformities of the hands were evident, with progressive resorption of distal and middle phalanges compared to earlier radiographs. Guglielmi et al. (2010) pointed out that similar, but more extensive, skeletal changes had been described in a 56-year-old Japanese woman who was the oldest MADA patient reported at that time (Kosho et al., 2007), and concluded that in MAD, osteolysis is not confined to the originally described sites (hands and clavicles), but may affect other skeletal regions.
Clinical Variability
Plasilova et al. (2004) reported 4 affected members of a consanguineous family from north India with a phenotype that included features of both MADA and Hutchinson-Gilford progeria syndrome (HGPS; 176670) associated with a homozygous mutation in the LMNA gene (K542N; 150330.0033). The patients showed uniform skeletal malformations such as acroosteolysis of the digits, micrognathia, and clavicular aplasia/hypoplasia, characteristic of MADA. They also showed hallmark features of progeria. Plasilova et al. (2004) suggested that autosomal recessive MADA and HGPS may represent a single disorder with varying degrees of severity.
Lombardi et al. (2007) identified a patient with an apparent MADA phenotype without clavicular hypoplasia or metabolic imbalances, and resembling limb-girdle myopathy. Clinical features included a hypoplastic mandible, acroosteolysis, pointed nose, partial loss of subcutaneous fat, and a progeric appearance. Due to the absence of clavicular dysplasia and normal metabolic profiles, generally associated with muscle hyposthenia and generalized hypotonia, the authors considered this phenotype an atypical laminopathy. The patient's cells showed nuclear shape abnormalities, accumulation and prelamin A, and irregular lamina thickness.
Van Esch et al. (2006) described a 44-year-old man of European descent who had a syndrome involving arthropathy, tendinous calcinosis, and progeroid features. The arthropathy affected predominantly the distal femora and proximal tibia in the knee with tendinous calcifications. Progeroid features included a small pinched nose, small lips, micrognathia with crowded teeth, cataract, and alopecia. He also had generalized lipodystrophy, and sclerodermatous skin. However, he had normal clavicles and no evidence of acroosteolysis. The authors concluded that he had a novel phenotype. He died at 44 years of age from Staphylococcus aureus sepsis resulting from infection of skin ulcers. Genetic analysis identified a homozygous mutation in the LMNA gene (S573L; 150330.0041). The patient's unaffected 15-year-old son and 70-year-old mother were both heterozygous carriers.
Zirn et al. (2008) reported a 7-year-old Turkish girl, born of consanguineous parents, who was homozygous for a mutation (R471C; 150330.0026) in the LMNA gene. She had a phenotype most consistent with an atypical form of MADA, including lipodystrophy, a progeroid appearance, and congenital muscular dystrophy with rigid spine syndrome. These latter features were reminiscent of Emery-Dreifuss muscular dystrophy (181350), although there was no cardiac involvement. She presented at age 10 months with proximal muscle weakness, contractures, spinal rigidity, and a dystrophic skeletal muscle biopsy. Characteristic progeroid features and features of lipodystrophy and mandibuloacral dysplasia were noted at age 3 years and became more apparent with age. Zirn et al. (2008) commented on the severity of the phenotype and emphasized the phenotypic variability in patients with LMNA mutations.
By analysis of 5 consanguineous Italian families with MAD, Novelli et al. (2002) demonstrated linkage of the disorder to chromosome 1q21.
In 9 affected patients from 5 consanguineous Italian families with MAD, Novelli et al. (2002) identified a homozygous mutation in the LMNA gene (R527H; 150330.0021). The authors noted that LMNA also causes several distinct disorders, including Dunnigan type familial partial lipodystrophy (151660), a condition that is characterized by subcutaneous fat loss and is invariably associated with insulin resistance and diabetes. Simha et al. (2003) noted that the patients of Novelli et al. (2002) had type A lipodystrophy.
In 2 of pedigrees with MAD and type A lipodystrophy, Simha et al. (2003) identified the homozygous R527H LMNA mutation.
In a Mexican American boy with MAD born of related parents, Shen et al. (2003) identified homozygosity for the R527H mutation. The authors noted that all the patients reported by Novelli et al. (2002) shared a common disease haplotype, but that the patients reported by Simha et al. (2003) and their Mexican American patient had different haplotypes, indicating independent origins of the mutation.
In 1 patient with an apparently typical HGPS phenotype who was 28 years old at the time that DNA was obtained, Cao and Hegele (2003) identified compound heterozygosity for 2 missense mutations in the LMNA gene (150330.0025 and 150330.0026); this patient was later determined (Brown, 2004) to have mandibuloacral dysplasia.
In a patient with a MADA-like phenotype but without clavicular hypoplasia or metabolic imbalances, Lombardi et al. (2007) found compound heterozygosity for missense mutations in the LMNA gene (150330.0021, 150330.0044).
Lombardi et al. (2008) detected significantly higher levels (approximately 4.7-fold) of the active enzyme forms of MMP9 (120361) in the serum of 5 patients with MADA compared to 16 controls. No significant differences were found for several other metalloproteinases. The findings suggested a pathogenic role for MMP9 in the skeletal manifestations of the disorder.
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