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Mandibuloacral Dysplasia Type B in an Infant A Rare Progeroid Genodermatosis FREE

Julia M. Kwan, MD1
[+] Author Affiliations
1Department of Dermatology, Naval Health Clinic Hawaii, Pearl Harbor
JAMA Dermatol. 2015;151(5):561-562. doi:10.1001/jamadermatol.2014.5068.
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Published online

Mandibuloacral dysplasia (MAD) type B is a rare genodermatosis with early-onset dermatologic, skeletal, and craniofacial abnormalities and long-term renal morbidity.

REPORT OF A CASE

A 5-month-old boy of non-consanguineous parents presented with congenital brown pigmentation on his ankles that progressed to the knees, shins, and wrists. Born at 35 weeks’ gestation via cesarean delivery, he had facial asymmetry and leg contractures initially attributed to breech positioning in utero. He had poor weight gain but normal vision and hearing. At age 3 months, he underwent a skeletal survey that revealed mandibular hypoplasia and osseous abnormalities of the clavicles, humeri, and tibia. Results of a chromosomal screen were negative. No known relations, including 2 paternal half-siblings, had similar findings.

Physical examination showed a cheerful boy with micrognathia, a small nose, prominent eyes, large, open fontanelles, and thin, contracted lower extremities (Figure, A). Nonindurated light brown patches were present on the wrists, bilateral tibias, and ankles. The clinical and radiologic findings suggested a progeroid laminopathy. An atypical progeroid syndrome was considered, but the patient’s young age favored MAD type B.

Place holder to copy figure label and caption
Figure.
Clinical Images of a Patient With Mandibuloacral Dysplasia

A, At age 5 months, the patient shows the classic findings of micrognathia, small thin nose, large prominent eyes, short clavicles, and thin extremities as well as light brown patches on the wrists, tibias, and ankles. B, At age 10 months, the patient shows progression of cutaneous findings, with more pronounced atrophic skin tautly stretched over an increasingly muscular-appearing lower leg.

Graphic Jump Location

Analysis of the ZMPSTE24 gene confirmed MAD type B, revealing a compound heterozygous mutation that combined a missense mutation (Asn265Ser) inherited from the patient’s mother with a nonsense mutation (Leu362Phefs*19) inherited from his father.

At age 10 months, his skin was notably thinner, appearing more tautly stretched over increasingly lipoatrophic lower legs (Figure, B). Acro-osteolysis was becoming apparent with noticeably shortened distal phalanges and broad, hypoplastic fingernails. His diagnosis prompted nephrologic and endocrinologic consultations and management for long-term morbidity.

DISCUSSION

MAD is an especially uncommon autosomal recessive disorder with phenotypic and genetic heterogeneity characterized by micrognathia, joint contractures, hypoplastic clavicles, acro-osteolysis, open fontanelles, mottled pigmentation, and failure to thrive. Phenotypic severity correlates with the level of prelamin accumulation or lack of mature lamin A1 that result from mutations in LMNA (encodes lamin A/C) or ZMPSTE24 (a zinc metalloproteinase that processes prelamin A to mature lamin A). Lamin is crucial for proper nuclear lamina formation. Subtypes A and B differ in the extent of lipodystrophy, age at presentation, and long-term sequelae.

Patients with MAD type A do not show characteristic syndromic features or partial lipodystrophy until age 4 or 5 years.1

MAD type B is rarer. To our knowledge, only 10 cases have been reported prior to the present one.16 Compound heterozygous nonsense and missense mutations in ZMPSTE241,35 predominate, with 1 report of a homozygous missense mutation in ZMPSTE246 and 1 case of a homozygous null ZMPSTE24 mutation combined with a “rescue” LMNA mutation.2 Dysmorphic progeroid features, mottled pigmentation, and joint contractures present early in infancy. Skeletal dysplasias develop by age 1 to 2 years. Generalized lipodystrophy presents variably from the toddler to teen years. Metabolic disease is poorly defined but has been reported in young adulthood.

Two unique long-term sequelae for MAD type B are progressive glomerulopathy and subcutaneous calcified nodules. Clinically relevant kidney disease presents in patients who have reached their 20s,1,3,6 but microhematuria with normal findings of kidney ultrasonography have been reported in early childhood.5 Calcified nodules start as early as age 2 years.1 Significantly, 2 patients in their late 20s or 30s have died from a combination of vascular calcifications and renal failure.3,6

Interestingly, though our patient has the same compound heterozygous mutation as was found in 2 other cases,2,3 their clinical presentations are not identical. Indeed, neither LMNA or ZMPSTE24 mutations were found in 3 other patients with MAD type B,1 suggesting that undiscovered mutations may modulate the clinical phenotype.

Dermatologists may be consulted to evaluate dyspigmentation but can be instrumental in the diagnosis of MAD type B by recognizing its earlier multisystem constellation of symptoms. Earlier diagnosis would alert physicians of the particular need, among others, for early renal monitoring. However, disease heterogeneity suggests that management should be tailored to phenotypic severity.

ARTICLE INFORMATION

Corresponding Author: Julia M. Kwan, MD, Department of Dermatology, Naval Health Clinic Hawaii, 480 Central Ave, Pearl Harbor, HI 96860 (Julia.kwan@med.navy.mil).

Published Online: January 28, 2015. doi:10.1001/jamadermatol.2014.5068.

Conflict of Interest Disclosures: None reported.

Disclaimer: The views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.

REFERENCES

Agarwal  AK, Fryns  JP, Auchus  RJ, Garg  A.  Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet. 2003;12(16):1995-2001.
PubMed   |  Link to Article
Shackleton  S, Smallwood  DT, Clayton  P,  et al.  Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype. J Med Genet. 2005;42(6):e36.
PubMed   |  Link to Article
Agarwal  AK, Zhou  XJ, Hall  RK,  et al.  Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency. J Investig Med. 2006;54(4):208-213.
PubMed   |  Link to Article
Denecke  J, Brune  T, Feldhaus  T,  et al.  A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS. Hum Mutat. 2006;27(6):524-531.
PubMed   |  Link to Article
Miyoshi  Y, Akagi  M, Agarwal  AK,  et al.  Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings. Clin Genet. 2008;73(6):535-544.
PubMed   |  Link to Article
Ben Yaou  R, Navarro  C, Quijano-Roy  S,  et al.  Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation. Eur J Hum Genet. 2011;19(6):647-654.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Clinical Images of a Patient With Mandibuloacral Dysplasia

A, At age 5 months, the patient shows the classic findings of micrognathia, small thin nose, large prominent eyes, short clavicles, and thin extremities as well as light brown patches on the wrists, tibias, and ankles. B, At age 10 months, the patient shows progression of cutaneous findings, with more pronounced atrophic skin tautly stretched over an increasingly muscular-appearing lower leg.

Graphic Jump Location

Tables

References

Agarwal  AK, Fryns  JP, Auchus  RJ, Garg  A.  Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet. 2003;12(16):1995-2001.
PubMed   |  Link to Article
Shackleton  S, Smallwood  DT, Clayton  P,  et al.  Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype. J Med Genet. 2005;42(6):e36.
PubMed   |  Link to Article
Agarwal  AK, Zhou  XJ, Hall  RK,  et al.  Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency. J Investig Med. 2006;54(4):208-213.
PubMed   |  Link to Article
Denecke  J, Brune  T, Feldhaus  T,  et al.  A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS. Hum Mutat. 2006;27(6):524-531.
PubMed   |  Link to Article
Miyoshi  Y, Akagi  M, Agarwal  AK,  et al.  Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings. Clin Genet. 2008;73(6):535-544.
PubMed   |  Link to Article
Ben Yaou  R, Navarro  C, Quijano-Roy  S,  et al.  Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation. Eur J Hum Genet. 2011;19(6):647-654.
PubMed   |  Link to Article

Correspondence

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