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Year : 2021  |  Volume : 22  |  Issue : 4  |  Page : 349-351

Case of mandibuloacral dysplasia with type B lipodystrophy

Department of Dermatology, LTMMC and LTMGH, Mumbai, Maharashtra, India

Date of Submission04-May-2020
Date of Decision25-Aug-2020
Date of Acceptance07-Feb-2021
Date of Web Publication01-Oct-2021

Correspondence Address:
Sanober Burzin Daruwalla
Department of Dermatology, LTMMC and GH, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpd.IJPD_77_20

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Introduction: Mandibuloacral dysplasia with type B lipodystrophy (MADB) caused by compound heterozygous mutation in the ZMPSTE24 gene is characterized by generalized lipodystrophy and short stature. Cutaneous manifestations of these disorders vary broadly. Case report: We present a genetically confirmed case of MAD Type B in a two year-old boy born out of second degree consanguinity. Discussion: The report aims to increase awareness of the rare condition and emphasize the utility of genetic analysis in differentiating it from other differentials with a phenotypic overlap.

Keywords: Lamin type A, Lamin C, Child, Progeria, Mandibuloacral dysplasia with type B lipodystrophy

How to cite this article:
Daruwalla SB, Dhurat RS, Ghate S, Arali R. Case of mandibuloacral dysplasia with type B lipodystrophy. Indian J Paediatr Dermatol 2021;22:349-51

How to cite this URL:
Daruwalla SB, Dhurat RS, Ghate S, Arali R. Case of mandibuloacral dysplasia with type B lipodystrophy. Indian J Paediatr Dermatol [serial online] 2021 [cited 2021 Nov 28];22:349-51. Available from: https://www.ijpd.in/text.asp?2021/22/4/349/327459

  Introduction Top

Mandibuloacral dysplasia (MAD) is an uncommon autosomal recessive disorder with phenotypic and genetic heterogeneity. Subtypes A and B differ in the extent of lipodystrophy, age at presentation, and long-term sequelae. Mandibuloacral dysplasia with type B lipodystrophy (MADB) can be caused by compound heterozygous mutation in the ZMPSTE24 gene (606480) on chromosome 1p34.

  Case Report Top

A two-year-old boy born of consanguineous parents (second degree) presented with dyspigmentation over neck, axilla and groin along with tightening of skin of lower limbs. He was second by order of birth, born at 37 weeks' gestation to a 28-year-old gravida 2 para 2 woman through cesarean delivery. Mother received adequate antenatal care and her antenatal testing scans at first and third trimesters were reported to be normal. His birth weight was appropriate for gestational age. However, his current weight and height was below the 3rd percentile for age. The first child succumbed at 2 months of age from unknown cause. Physical examination revealed a cheerful boy with micrognathia, prominent eyes, large, open fontanelles, and prominent veins visible over the face and trunk giving a progeroid appearance [Figure 1]a. Atrophic, sclerodermic skin with mottled pigmentation was seen over the neck, axilla and both lower limbs [Figure 1]b. Skin appeared taut and stretched over bilateral lower limbs and trunk. Lipoatrophy over the entire body more pronounced over the lower limbs was noticed [Figure 1]c. Biochemical investigations, renal function tests, glucose levels were within normal limits. Since a clinical differential of  Hutchinson-Gilford progeria More Details syndrome was kept, complete cardiac examination and echocardiogram was done, that returned no abnormalities. Skeletal survey revealed open fontanelles with failure of fusion of skull sutures, multiple wormian bones in the left parieto-occipital region and hypoplasia of the maxilla and mandible with crowding of teeth [Figure 2]. Osteolysis of lateral ends of bilateral clavicles, osteopenia of bones and old healed fracture of the proximal shaft of right humerus was noted along with acro-osteolysis of the terminal phalanges of the hand. Since mother was interested in conceiving again, clinical exome sequencing of the child was performed which revealed a homozygous 3 base deletion on exon 8 of ZMPSTE24 gene (chr1:g. 40751689_40751691delATC; Depth: ×87) resulting in an in-frame mutation observed in MAD Type B. Parents received appropriate genetic counseling for future conception.
Figure 1: (a) Cheerful face with micrognathia and prominent veins visible over the face giving a progeroid appearance. (b) Mottled pigmentation of the left axilla. (c) Shiny, taut and stretched skin over bilateral lower limbs and old scars over bilateral knees due to repeated falls

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Figure 2: (a) X-ray skull showing open fontanelles with failure of fusion of skull sutures, multiple wormian bones in the left parieto-occipital region and hypoplasia of the maxilla and mandible with crowding of teeth (AP and lateral view). (b) Skeletal survey showing osteolysis of lateral ends of bilateral clavicles, osteopenia of bones and old healed fracture of the proximal shaft of right humerus

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  Discussion Top

MAD is a rare autosomal recessive condition that was first mistakenly diagnosed as cleidocranial dysplasia.[1] Further research identified two types of MAD based on the type of body fat distribution pattern-MADA and MADB. In MADA (OMIM #248370), the distribution of fat throughout the body is altered with degeneration of subcutaneous adipose tissue in torso and limbs and accumulation on the face, neck and trunk which is similar to that described in patients with Dunnigan-type familial partial lipodystrophy (FPLD2; OMIM #151660).[2] MADB (OMIM #608612), is characterized with generalized lipodystrophy with almost complete loss of subcutaneous fat.[3] Agarwal et al. noted that this generalized lipodystrophy affecting the extremities, trunk, and face, contributes to the “progeroid” appearance.[4] The features typical of MADA include mandibular hypoplasia, dental crowding, clavicular resorption, acral osteolysis, skin abnormalities and partial lipodystrophy.[2] Mandibular hypoplasia, dental crowding, premature tooth eruption, clavicular resorption, acral osteolysis, skin abnormalities including absent or sparse hair (total or subtotal alopecia), generalized lipodystrophy and short stature are clinical signs of MADB, which is also associated with more pronounced accelerated ageing.[4] Two unique long-term sequelae for MADB are progressive glomerulopathy and subcutaneous calcified nodules. Clinically relevant kidney disease presents in patients who have reached their 20s, but microhematuria with normal findings on renal ultrasonography has been reported in early childhood. Calcified nodules are seen as early as two years of age.[5] Haye et al. reported that ZMPSTE24 plays a specific role in intramembranous ossification and that the failure of fusion of the occipital bone may be a useful diagnostic sign for MADB, distinguishing it from MADA.[6]

The genetic defect linked to type A pattern of lipodystrophy includes mutations in LMNA gene and to MADB includes mutations of the zinc metalloproteinase ZMPSTE24 gene.[2],[4] The protein produced from the ZMPSTE24 gene is involved in the processing of Lamin A and Lamin C which act as supporting components of the nuclear envelope in cells. Mutations in the ZMPSTE24 gene lead to accumulation of prelamin A and a shortage of the mature protein.[7] Prelamin A accumulation in MAD affects adipogenesis, bone differentiation and cellular response to stress. Mutations of ZMPSTE24 gene result in a total or partial loss of function of the enzymatic activity of the encoded protein, thereby giving rise to diverse clinical conditions depending on the degree of prelamin A processing impairment. This may also explain why some cases of MADB develop progeroid features.

In addition, the discovery of a new gene association in 2013 identified DNA polymerase delta gene (POLD1) mutations as the cause of a new progeroid disorder characterized by mandibular hypoplasia, deafness and generalized lipodystrophy (MDPL).[8] MDPL is being considered as a variant of MAD phenotype, with generalized lipodystrophy, osteopenia, accelerated ageing, hair abnormalities, and short stature as recurring phenotypes.[9]

In the present case, Hutchinson-Gilford progeria syndrome and familial partial lipodystrophy (FPL) were other diagnostic possibilities.

Because of overlapping clinical features between these diagnostic considerations, genetic testing helped in making a conclusive diagnosis.

Hitzert et al. studied the features of patients with MADB from the remote tropical rainforest of inland Suriname and defined criteria for use in settings with limited or no access to genetic testing. Major criteria were: Short stature, clavicular hypoplasia, delayed closure of cranial sutures, high palate, mandibular hypoplasia, dental crowding, acro-osteolysis of the distal phalanges, hypoplastic nails, brittle and/or sparse hair, mottled pigmentation, atrophic and sclerodermic skin, and calcified skin nodules. Minor criteria were (generalized or partial) lipoatrophy of the extremities, joint contractures and shortened phalanges. Based on their detailed clinical observations, and a review of previously described cases, they proposed that the clinical diagnosis of MADB is highly likely if a patient exhibits ≥4 major clinical criteria OR ≥3 major clinical criteria and ≥2 minor clinical criteria.[10]

Cutaneous manifestations in these genetic disorders vary broadly and require dermatology referral to identify these cases early and test for other associated metabolic derangement or multisystemic involvement. Phenotypic heterogeneity of the disease necessitates genetic confirmation of the diagnosis.

Declaration of consent

The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s) of the patient. In the form the parent(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


We would like to thank Dr. Deepak Parikh for his valuable guidance and support and Dr. Sahana Srinivas for her help in genetic testing.

Financial support and sponsorship

Indian Society of Pediatric Dermatology supported and contributed for the funding of genetic testing.

Conflicts of interest

There are no conflicts of interest.

  References Top

Cavallazzi C, Cremoncini R, Quadri A. On a case of cleidocranial dysostosis. Riv Clin Pediatr 1960;65:312-26.  Back to cited text no. 1
Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D'Apice MR, Massart C, et al. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet 2002;71:426-31.  Back to cited text no. 2
Simha V, Garg A. Body fat distribution and metabolic derangements in patients with familial partial lipodystrophy associated with mandibuloacral dysplasia. J Clin Endocrinol Metab 2002;87:776-85.  Back to cited text no. 3
Agarwal AK, Fryns JP, Auchus RJ, Garg A. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet 2003;12:1995-2001.  Back to cited text no. 4
Kwan JM. Mandibuloacral dysplasia type B in an infant: A rare progeroid genodermatosis. JAMA Dermatol 2015;151:561-2.  Back to cited text no. 5
Haye D, Dridi H, Levy J, Lambert V, Lambert M, Agha M, et al. Failure of ossification of the occipital bone in mandibuloacral dysplasia type B. Am J Med Genet A 2016;170:2750-5.  Back to cited text no. 6
OMIM Entry - # 608612 - Mandibuloacral dysplasia with type b lipodystrophy; MADB [Internet]. Omim.org. 2020. Available from: https://omim.org/entry/608612. [cited 2020 Mar 10].  Back to cited text no. 7
Weedon MN, Ellard S, Prindle MJ, Caswell R, Lango Allen H, Oram R, et al. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat Genet 2013;45:947-50.  Back to cited text no. 8
Cenni V, D'Apice MR, Garagnani P, Columbaro M, Novelli G, Franceschi C, et al. Mandibuloacral dysplasia: A premature ageing disease with aspects of physiological ageing. Ageing Res Rev 2018;42:1-3.  Back to cited text no. 9
Hitzert MM, van der Crabben SN, Baldewsingh G, van Amstel HKP, van den Wijngaard A, van Ravenswaaij-Arts CMA, et al. Mandibuloacral dysplasia type B (MADB): A cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines. Orphanet J Rare Dis 2019;14:294.  Back to cited text no. 10


  [Figure 1], [Figure 2]


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