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Mandibuloacral dysplasia with type A lipodystrophy(MADA)

MedGen UID:
1757618
Concept ID:
C5399785
Disease or Syndrome
Synonyms: CRANIOMANDIBULAR DERMATODYSOSTOSIS; Lipodystrophy, type A, associated with mandibuloacral dysplasia; MADA
SNOMED CT: Mandibuloacral dysostosis co-occurrent with type A lipodystrophy (1003431005); Mandibuloacral dysplasia with type A lipodystrophy (1003431005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): LMNA (1q22)
 
Monarch Initiative: MONDO:0009557
OMIM®: 248370
Orphanet: ORPHA90153

Definition

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). [from OMIM]

Clinical features

From HPO
Coxa valga
MedGen UID:
116080
Concept ID:
C0239137
Finding
Coxa valga is a deformity of the hip in which the angle between the femoral shaft and the femoral neck is increased compared to age-adjusted values (about 150 degrees in newborns gradually reducing to 120-130 degrees in adults).
Short distal phalanx of finger
MedGen UID:
326590
Concept ID:
C1839829
Finding
Short distance from the end of the finger to the most distal interphalangeal crease or the distal interphalangeal joint flexion point. That is, hypoplasia of one or more of the distal phalanx of finger.
Osteolytic defects of the distal phalanges of the hand
MedGen UID:
341480
Concept ID:
C1849547
Finding
Acroosteolysis of distal phalanges (feet)
MedGen UID:
871254
Concept ID:
C4025739
Anatomical Abnormality
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Postnatal growth retardation
MedGen UID:
395343
Concept ID:
C1859778
Finding
Slow or limited growth after birth.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Calcinosis
MedGen UID:
709
Concept ID:
C0006663
Finding
Formation of calcium deposits in any soft tissue.
Lipodystrophy
MedGen UID:
6111
Concept ID:
C0023787
Disease or Syndrome
Degenerative changes of the fat tissue.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Joint stiffness
MedGen UID:
56403
Concept ID:
C0162298
Sign or Symptom
Joint stiffness is a perceived sensation of tightness in a joint or joints when attempting to move them after a period of inactivity. Joint stiffness typically subsides over time.
Delayed cranial suture closure
MedGen UID:
75805
Concept ID:
C0277828
Finding
Infants normally have two fontanels at birth, the diamond-shaped anterior fontanelle at the junction of the coronal and sagittal sutures, and the posterior fontanelle at the intersection of the occipital and parietal bones. The posterior fontanelle usually closes by the 8th week of life, and the anterior fontanel closes by the 18th month of life on average. This term applies if there is delay of closure of the fontanelles beyond the normal age.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Elbow flexion contracture
MedGen UID:
98367
Concept ID:
C0409338
Acquired Abnormality
An elbow contracture that limits the ability of the elbow joint to be extended (straightened), meaning that the elbow is fixed in an flexed (bent) position.
Short clavicles
MedGen UID:
96529
Concept ID:
C0426799
Congenital Abnormality
Reduced length of the clavicles.
Camptodactyly
MedGen UID:
195780
Concept ID:
C0685409
Congenital Abnormality
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers or toes cannot be extended to 180 degrees by either active or passive extension.
Progressive clavicular acroosteolysis
MedGen UID:
324869
Concept ID:
C1837757
Finding
Progressive bone resorption in the distal part of the clavicle.
Loss of subcutaneous adipose tissue in limbs
MedGen UID:
325248
Concept ID:
C1837764
Finding
Loss (disappearance) of previously present subcutaneous fat tissue in arm or leg.
Down-sloping shoulders
MedGen UID:
346461
Concept ID:
C1856872
Finding
Low set, steeply sloping shoulders.
Reduced subcutaneous adipose tissue
MedGen UID:
387876
Concept ID:
C1857657
Finding
A reduced amount of fat tissue in the lowest layer of the integument. This feature can be appreciated by a reduced skinfold thickness.
Wormian bones
MedGen UID:
766814
Concept ID:
C3553900
Congenital Abnormality
The presence of extra bones within a cranial suture. Wormian bones are irregular isolated bones which appear in addition to the usual centers of ossification of the cranium.
Hypercholesterolemia
MedGen UID:
5687
Concept ID:
C0020443
Disease or Syndrome
An increased concentration of cholesterol in the blood.
Hyperglycemia
MedGen UID:
5689
Concept ID:
C0020456
Disease or Syndrome
An increased concentration of glucose in the blood.
Hyperlipidemia
MedGen UID:
5692
Concept ID:
C0020473
Disease or Syndrome
An elevated lipid concentration in the blood.
Impaired glucose tolerance
MedGen UID:
852424
Concept ID:
C0151671
Finding
An abnormal resistance to glucose, i.e., a reduction in the ability to maintain glucose levels in the blood stream within normal limits following oral or intravenous administration of glucose.
Insulin-resistant diabetes mellitus
MedGen UID:
163439
Concept ID:
C0854110
Disease or Syndrome
A type of diabetes mellitus related not to lack of insulin but rather to lack of response to insulin on the part of the target tissues of insulin such as muscle, fat, and liver cells. This type of diabetes is typically associated with increases both in blood glucose concentrations as well as in fasting and postprandial serum insulin levels.
Dental crowding
MedGen UID:
11850
Concept ID:
C0040433
Finding
Changes in alignment of teeth in the dental arch
Premature loss of teeth
MedGen UID:
66678
Concept ID:
C0232513
Finding
Exfoliation of a tooth more than 2 SD earlier than the normal age for the deciduous teeth and not related to traume or neglect. Exfoliation of a permanent tooth is per se abnormal.
Hypoplasia of teeth
MedGen UID:
852449
Concept ID:
C0235357
Congenital Abnormality
Developmental hypoplasia of teeth.
Convex nasal ridge
MedGen UID:
66809
Concept ID:
C0240538
Finding
Nasal ridge curving anteriorly to an imaginary line that connects the nasal root and tip. The nose appears often also prominent, and the columella low.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Bird-like facies
MedGen UID:
325243
Concept ID:
C1837758
Finding
Narrow nasal ridge
MedGen UID:
373404
Concept ID:
C1837761
Finding
Decreased width of the nasal ridge.
Sparse scalp hair
MedGen UID:
346499
Concept ID:
C1857042
Finding
Decreased number of hairs per unit area of skin of the scalp.
Full cheeks
MedGen UID:
355661
Concept ID:
C1866231
Finding
Increased prominence or roundness of soft tissues between zygomata and mandible.
Increased adipose tissue around the neck
MedGen UID:
871356
Concept ID:
C4025850
Finding
An increased amount of subcutaneous fat tissue around the neck.
Increased facial adipose tissue
MedGen UID:
871372
Concept ID:
C4025868
Finding
An increased amount of subcutaneous fat tissue in the face.
Acanthosis nigricans
MedGen UID:
54
Concept ID:
C0000889
Disease or Syndrome
A dermatosis characterized by thickened, hyperpigmented plaques, typically on the intertriginous surfaces and neck.
Alopecia
MedGen UID:
7982
Concept ID:
C0002170
Finding
A noncongenital process of hair loss, which may progress to partial or complete baldness.
Dermal atrophy
MedGen UID:
101793
Concept ID:
C0151514
Disease or Syndrome
Partial or complete wasting (atrophy) of the skin.
Onychogryposis
MedGen UID:
82671
Concept ID:
C0263537
Disease or Syndrome
Nail that appears thick when viewed on end.
Poikiloderma
MedGen UID:
97905
Concept ID:
C0392777
Disease or Syndrome
Poikiloderma refers to a patch of skin with (1) reticulated hypopigmentation and hyperpigmentation, (2) wrinkling secondary to epidermal atrophy, and (3) telangiectasias.
Mottled pigmentation
MedGen UID:
163653
Concept ID:
C0860439
Finding
Patchy and irregular skin pigmentation.
Hyperinsulinemia
MedGen UID:
43779
Concept ID:
C0020459
Disease or Syndrome
An increased concentration of insulin in the blood.
Proptosis
MedGen UID:
41917
Concept ID:
C0015300
Disease or Syndrome
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMandibuloacral dysplasia with type A lipodystrophy

Professional guidelines

PubMed

Cenni V, Capanni C, Mattioli E, Columbaro M, Wehnert M, Ortolani M, Fini M, Novelli G, Bertacchini J, Maraldi NM, Marmiroli S, D'Apice MR, Prencipe S, Squarzoni S, Lattanzi G
Aging (Albany NY) 2014 Sep;6(9):755-70. doi: 10.18632/aging.100680. PMID: 25324471Free PMC Article
Camozzi D, D'Apice MR, Schena E, Cenni V, Columbaro M, Capanni C, Maraldi NM, Squarzoni S, Ortolani M, Novelli G, Lattanzi G
Histochem Cell Biol 2012 Oct;138(4):643-51. Epub 2012 Jun 17 doi: 10.1007/s00418-012-0977-5. PMID: 22706480Free PMC Article

Recent clinical studies

Etiology

Jéru I, Nabil A, El-Makkawy G, Lascols O, Vigouroux C, Abdalla E
Genes (Basel) 2021 Sep 26;12(10) doi: 10.3390/genes12101508. PMID: 34680903Free PMC Article
Camozzi D, Capanni C, Cenni V, Mattioli E, Columbaro M, Squarzoni S, Lattanzi G
Nucleus 2014 Sep-Oct;5(5):427-40. doi: 10.4161/nucl.36289. PMID: 25482195Free PMC Article
Capanni C, Squarzoni S, Cenni V, D'Apice MR, Gambineri A, Novelli G, Wehnert M, Pasquali R, Maraldi NM, Lattanzi G
Cell Cycle 2012 Oct 1;11(19):3568-77. Epub 2012 Aug 30 doi: 10.4161/cc.21869. PMID: 22935701Free PMC Article

Diagnosis

Ozer L, Unsal E, Aktuna S, Baltaci V, Celikkol P, Akyigit F, Sen A, Ayvaz O, Balci S
Clin Dysmorphol 2016 Jul;25(3):91-7. doi: 10.1097/MCD.0000000000000132. PMID: 27100822
Yassaee VR, Khojaste A, Hashemi-Gorji F, Ravesh Z, Toosi P
Gene 2016 Feb 10;577(1):8-13. Epub 2015 Nov 19 doi: 10.1016/j.gene.2015.08.071. PMID: 26602028

Therapy

Cenni V, Capanni C, Mattioli E, Columbaro M, Wehnert M, Ortolani M, Fini M, Novelli G, Bertacchini J, Maraldi NM, Marmiroli S, D'Apice MR, Prencipe S, Squarzoni S, Lattanzi G
Aging (Albany NY) 2014 Sep;6(9):755-70. doi: 10.18632/aging.100680. PMID: 25324471Free PMC Article

Prognosis

Yassaee VR, Khojaste A, Hashemi-Gorji F, Ravesh Z, Toosi P
Gene 2016 Feb 10;577(1):8-13. Epub 2015 Nov 19 doi: 10.1016/j.gene.2015.08.071. PMID: 26602028
Luo DQ, Wang XZ, Meng Y, He DY, Chen YM, Ke ZY, Yan M, Huang Y, Chen DF
BMC Pediatr 2014 Oct 7;14:256. doi: 10.1186/1471-2431-14-256. PMID: 25286833Free PMC Article
Ben Yaou R, Navarro C, Quijano-Roy S, Bertrand AT, Massart C, De Sandre-Giovannoli A, Cadiñanos J, Mamchaoui K, Butler-Browne G, Estournet B, Richard P, Barois A, Lévy N, Bonne G
Eur J Hum Genet 2011 Jun;19(6):647-54. Epub 2011 Jan 26 doi: 10.1038/ejhg.2010.256. PMID: 21267004Free PMC Article

Clinical prediction guides

Carvalho AA, Machado RA, Maia CMF, Santos LAND, Martelli DRB, Coletta RD, Martelli Júnior H
Rev Paul Pediatr 2024;42:e2022189. Epub 2024 May 27 doi: 10.1590/1984-0462/2024/42/2022189. PMID: 38808865Free PMC Article
Jéru I, Nabil A, El-Makkawy G, Lascols O, Vigouroux C, Abdalla E
Genes (Basel) 2021 Sep 26;12(10) doi: 10.3390/genes12101508. PMID: 34680903Free PMC Article
Elouej S, Harhouri K, Le Mao M, Baujat G, Nampoothiri S, Kayserili H, Menabawy NA, Selim L, Paneque AL, Kubisch C, Lessel D, Rubinsztajn R, Charar C, Bartoli C, Airault C, Deleuze JF, Rötig A, Bauer P, Pereira C, Loh A, Escande-Beillard N, Muchir A, Martino L, Gruenbaum Y, Lee SH, Manivet P, Lenaers G, Reversade B, Lévy N, De Sandre-Giovannoli A
Nat Commun 2020 Sep 11;11(1):4589. doi: 10.1038/s41467-020-18146-9. PMID: 32917887Free PMC Article
Yassaee VR, Khojaste A, Hashemi-Gorji F, Ravesh Z, Toosi P
Gene 2016 Feb 10;577(1):8-13. Epub 2015 Nov 19 doi: 10.1016/j.gene.2015.08.071. PMID: 26602028
Ben Yaou R, Navarro C, Quijano-Roy S, Bertrand AT, Massart C, De Sandre-Giovannoli A, Cadiñanos J, Mamchaoui K, Butler-Browne G, Estournet B, Richard P, Barois A, Lévy N, Bonne G
Eur J Hum Genet 2011 Jun;19(6):647-54. Epub 2011 Jan 26 doi: 10.1038/ejhg.2010.256. PMID: 21267004Free PMC Article

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