5473_Genetic 4/2005
20.10.2005
9:07
Page 353
GENETIC COUNSELING, Vol. 16, No 4, 2005, pp. 353-362
MANDIBULOACRAL DYSPLASIA: A REPORT OF TWO EGYPTIAN CASES BY H.H. AFIFI 1 AND H.T. EL- BASSYOUNI 1 Summary : Mandibuloacral dysplasia: a report of two egyptian cases: Mandibuloacral dysplasia (MAD) is a rare disorder. Only 35 patients, coming from 22 families, have been reported worldwide. We report on two Egyptian unrelated girls with MAD. The first patient presented at the age of 5 years with acral defect and partial alopecia. The second patient presented at the age of 17 years with progressive micrognathia and loss of subcutaneous fat from the limbs. Physical examination detected the craniofacial, skeletal and cutaneous changes characteristic of MAD. Both patients were short with progeroid facies and loss of subcutaneous fat from the extremities, which fits lipodystrophy type A pattern. Radiological examination revealed delayed closure of cranial sutures, hypoplastic mandible, hypoplastic clavicles, and acroosteolysis. Both patients had normal glucose tolerance, but had fasting and post-prandial hyperinsulinemia, suggestive of insulin resistance. One patient had elevated serum triglycerides and low normal cholesterol levels, while the other patient had normal levels. Serum leptin was normal in both patients. We review the literature on mandibuloacral dysplasia and discuss the differential diagnosis. Key-words : Mandibuloacral dysplasia – Progeroid facies – Micrognathia.
INTRODUCTION Cavallazzi et al. in 1960 (6), were probable the first to report a syndrome characterized by mandibular hypoplasia, delayed cranial suture closure, hypoplastic clavicles, cutaneous atrophy and accroosteolysis. Later on, Young et al. in 1971 (29), reported two male patients with similar features and designated the syndrome as “mandibuloacral dysplasia.” Although the true incidence of the syndrome is unknown at present, it is believed to be very rare. Mandibuloacral dysplasia (MAD ; MIM 248370 at OMIM) (19) is a phenotypically and genetically heterogenous rare autosomal recessive disorder. It is characterized by postnatal growth retardation, craniofacial anomalies (such as : mandiblular hypoplasia, pointed/beaked nose, and prominent eyes), skeletal malformations (such as : clavicle hypoplasia, accroosteolysis, and delayed closure of cranial sutures and fontanels), cutaneous changes (such as : thin skin, partial alopecia, hypo- and hyperpigmentation patches/spots) and lipodystrophy. Other features less commonly associated with MAD are hypogonadism or delayed puberty, bilateral sensory neural deafness, high arched palate and cutaneous calcinosis (17, 20).
(1) Clinical Genetics Department, National Research Centre, Cairo, Egypt..
353
5473_Genetic 4/2005
20.10.2005
9:07
Page 354
GENETIC COUNSELING
Two patterns of lipodystrophy have been identified in patients with MAD. Partial lipodystrophy (type A pattern) is characterized by loss of subcutaneous fat from the extremities with normal or slight excess in neck and truncal regions ; whereas patients with type B pattern have a more generalized loss of subcutaneous fat involving the face, trunk and extremities (12, 21, 24). Recently, it has been shown that MAD type A is caused by mutations in the gene encoding lamin A/C at chromosome 1q21.2 (18, 22), while type B is caused by mutations in the ZMPSTE24 gene at 1p34 (1). Up till now, only 35 cases of MAD, coming from 22 families, were reported worldwide (Table I). Four of these families had MAD type B ; and seven of the 22 families were of Italian origin (7, 11, 15, 19, 21, 24, 26). We report on two unrelated Egyptian girls with MAD type A. We review the literature on the subject and discuss the differential diagnosis. Table I : Clinical features of our patients and the published cases with MAD. Features
Patient 1
Age of onset Sex Growth retardation Micrognathia Bird-like facies Clavicular hypoplasia Acroosteolysis
4y F + + + + +
Wide cranial suture/ Open fontanel
+
Skin atrophy Hypo- & hyperpigmentation Joint stiffness Lipodystrophy Excess fat over the neck
+ + -
Patient 2 12 y F + + + + +
Previous cases %
(n = 35)a 4.8 ± 2.7 22 M, 13 F 28/33 33/34 30/34 28/35 31/35
84.8 97 88 80 88.6
23/27
85.2
27/31 26/31 26/33 19/21 6/20
87 83.8 83.8 90.5 30
+ + + + + +
Previous cases (7, 11, 15, 19, 21, 24, 26). a Numerator signifies number of patients with the clinical feature ; denominator shows the total number of patients.
CLINICAL REPORT PATIENT 1 A 5-year-old Egyptian girl, who was the 5th offspring of healthy consanguineous parents, was examined by the authors. The mother and father were 27 and 34 years old, respectively, at the time of her birth. The pregnancy and delivery were uneventful. She was born at 39 weeks gestation with birth weight of 3.5 kg (+ 1 SD) and birth length of 51 cm (+ 0.5 SD). Developmental milestones were normal during infancy and early childhood. The parents first noticed rounding of her fingertips and partial alopecia at age 4 years. She also developed progressive micrognathia. 354
5473_Genetic 4/2005
20.10.2005
9:07
Page 355
H.H. AFIFI ET AL., Mandibuloacral dysplasia
Physical examination revealed a weight of 10 kg (- 3.1 SD), a height of 88.2 cm (- 4.2 SD), and a head circumference of 48.2 cm (- 2 SD). The eyes appeared large and the nose was pointed, while scalp hair was sparse and lusterless. She had full cheeks and micrognathia (Fig. 1). Oral examination showed high arched palate, tongue devoid of papillae and hypoplastic teeth. There was loss of subcutaneous fat from both upper and lower limbs. Fingertips were short and rounded giving the impression of accroosteolysis of the terminal phalanges. Feet showed broad terminal phalanges. Skin examination detected hypo- and hyperpigmentated spots over the abdomen, buttocks and back. Neurological, abdominal, chest and heart examinations detected no abnormality. Genital examination revealed normal female external genitalia. Radiological examination of the skull and hands showed delayed closure of cranial sutures, hypoplastic mandible (Figs 2 & 3) and accroosteolysis of the distal phalanges (Fig. 4). Chest X-ray revealed hypoplastic clavicles and normal lungs (Fig. 5). Calculated bone age, using Tanner-White method, corresponded to the patient’s chronological age, at the time of X-ray examination. Evaluation of IQ, using WPPSI-R test (Wechsler Preschool and Primary Scale of Intelligence – Revised) detected normal average mentality. Complete
Figure 1 : Patient 1 and her normal older brother. Prominent eyes, full cheeks, mandibular hypoplasia, sparse hair and lipodystrophy are noted in the patient.
Figure 2 : Patient 1, lateral view of the skull. Open cranial sutures and mandibular hypoplasia are noted.
355
5473_Genetic 4/2005
20.10.2005
9:07
Page 356
GENETIC COUNSELING
audiometry revealed no abnormality. Chromosomal analysis using Gbanding technique showed normal 46,XX female karyotype. Echo heart detected no abnormality. Total blood count (4.5 million/UL) was within normal ranges. She had normal fasting plasma glucose concentration (4.1 mmol/L), normal fasting plasma insulin (85 pmol/L) and normal glu-
Figure 3 : Patient 1, anterior view of the skull. Open cranial sutures are noted.
Figure 5 : Patient 1, chest X-ray showing hypoplastic clavicles.
356
Figure 4 : Patient 1, hands X-ray showing acroosteolysis of the distal phalanges.
5473_Genetic 4/2005
20.10.2005
9:07
Page 357
H.H. AFIFI ET AL., Mandibuloacral dysplasia
cose tolerance. However, oral glucose-tolerance test revealed marked basal and post-prandial hyperinsulinemia suggestive of insulin resistance. Her fasting serum cholesterol (4.15 mmol/L), triglycerides (1.36 mmol/L), and leptin (5.12 ng/ml) levels were unremarkable. The thyroid profile (free T3 = 4.2 pmol/L, free T4 = 15.3 pmol/L & TSH = 2.7 mIU/L) was normal.
PATIENT 2 A 17-year-old Egyptian girl, who was the only child of healthy first cousin parents, was examined by the authors. The mother and father were 21 and 24 years old, respectively, at the time of her birth. The pregnancy and delivery were uneventful. She was born at 41 weeks gestation with an average birth weight and height. Developmental milestones were normal during infancy and childhood. Menarche began at 14 years and she had regular menstrual cycles. At the age of 12 years, the patient noticed progressive micrognathia and loss of subcutaneous fat from the limbs, with excess fat around the face and submental region. Later she noted sparse scalp hair, brittle nails and rounding of her fingertips and toe-tips. Physical examination revealed a weight of 25.5 kg (- 3.2 SD), a height of 135 cm (- 4.5 SD), and head circumference of 52 cm (- 1.99 SD). The eyes were proptotic and the nose was beaked. She had partial alopecia and micrognathia (Fig. 6). Oral examination showed high arched palate,
A
B
Figure 6: Patient 2, A) face & B) profile showing protruded eyes, beaked nose, mandibular hypoplasia and sparse hair.
357
5473_Genetic 4/2005
20.10.2005
9:07
Page 358
GENETIC COUNSELING
delayed eruption of teeth and malposed teeth. There was loss of subcutaneous fat from both the upper and lower extremities with increased fat deposition over the face and neck, and with double chin. Skin examination showed hypo- and hyperpigmentated spots over the abdomen, buttocks and thighs with atrophic changes over the hands. Fingers and toes had broad terminal phalanges with dysplastic nails (Fig. 7) and stiffness of joints. Breast development was Tanner stage 4, while axillary hair was Tanner stage 1, and pubic hair was Tanner stage 5. There was bilateral axillary acanthosis. Genital examination revealed normal female external genitalia. Neurological, abdominal, chest and heart examinations detected no abnormality.
Figure 7 : Patient 2, broad terminal phalanges of the feet.
Radiological examination of the skull and chest revealed delayed closure of the anterior fontanel, hypoplastic mandible (Fig. 8) and hypoplastic clavicles especially at their lateral ends (Fig. 9). Evaluation of IQ, using Wechsler test, detected normal average mentality. Complete audiometry revealed no abnormality. Chromosomal analysis using Gbanding technique showed normal 46,XX female karyotype. Total blood count (3.5 million/uL) showed mild anaemia. Her fasting plasma glucose (5.1 mmol/L) was normal. She had normal glucose tolerance, but had elevated fasting insulin (198 pmol/L) and post-prandial hyperinsulinemia, where the peak plasma insulin concentration was 835 pmol/L, indicating insulin resistance. Her serum triglycerides level (4.10 mmol/L) was elevated, while her cholesterol level (4.08 mmol/L) was normal. The plasma leptin level (12.28 ng/ml) was normal for her age and sex. Thyroid profile (free T3 = 6.3 pmol/L, free T4 = 20.4 pmol/L & TSH = 4.4 mIU/L) was normal. Evaluation of serum FSH (8.2 IU/L), LH (20.5 IU/L), estradiol (468 pmol/L), and progesterone (2.8 nmol/L) revealed no abnormality. 358
5473_Genetic 4/2005
20.10.2005
9:07
Page 359
H.H. AFIFI ET AL., Mandibuloacral dysplasia
Figure 8 : Patient 2, lateral view of the skull. Open cranial sutures and mandibular hypoplasia are noted.
Figure 9 : Patient 2, chest X-ray showing hypoplastic clavicles.
DISCUSSION Mandibuloacral dysplasia is not only a rare disorder, but also has protean manifestations involving mainly the skeleton, skin, and adipose tissue. Table I summarizes the clinical features of the 35 published patients with MAD (7, 11, 15, 19, 21, 24, 26). Many of the clinical features of MAD overlap with other progeroid syndromes (14). In all MAD patients the onset of the disease was between 3-14 years, with facial and digital changes being the earliest manifestations (11, 25). However, Vantrappen et al. (27) reported a 1-year-old boy with MAD. The combination of progressive mandibular and digital changes, as well as the skin changes, is likely heterogenous and not pathognomonic of MAD (Table II). Patients with MAD have previously been described as having HGPS and Werner syndrome. Hoeffel et al. (15) described a 3-year-old girl as having HGPS, when she was reexamined at the age of 7 years, the diagnosis was changed to MAD (15). The blood chemistry of the girl showed insulin resistance and its associated metabolic abnormalities, which are important features of MAD. Indeed, there are striking clinical similarities between MAD and HGPS, however, unlike HGPS, the mode of inheritance in MAD is autosomal recessive and the alopecia is partial (Table II). 359
360 Osteo-porosis -
+
+ Normal -
Hypo- & hyper pigmentation
Frontal bossing, absent ear lobule, premature atherosclerosis
+ + and wrinkles Small crowded & delayed eruption Mucosal atrophy & premature loss of teeth Hoarse voice, DM, scleroderma-like skin changes
+ -
±
Osteo-porosis -
-
-
-
Premature loss & graying -
Pinched
8p12 – p11.2 Average Cataract
Thin skin & visible veins
_
+
-
Normal -
+
±
-
Partial alopecia +
Beaked
Average + Prominent
–
sc = subcutaneous , + means present, - means absent, ± means may be present
Others
Dental anomalies
Loss of sc fat Skin atrophy
+ mild
+
+
-
+
+ interphalangeal + + over extremities Premature loss of teeth & crowded teeth
+
+
LBW or average ++ Prominent cataract Beaked/ pinched Early baldness
1q21.2
277700
Acrogeria Gottron type 201200
Brachy-cephaly, midface hypoplasia
+ over scalp & nose ± neonatal teeth
-
+ Normal -
+
-
-
+
Average or LBW + Small squint cataract Pinched/ beaked Hypo-trichosis
–
234100
HallermannStreiff
Midface hypoplasia, synophrys, multiple fractures
Premature loss of teeth
-
-
+ Osteo-porosis -
+ and large sella turcica
+
-
+
Average + Mild exophthalmos exoNo especial character Hirsutism
–
102500
Hajdu- Cheney
Enamel hypoplasia & delayed eruption Increase fractures, absent frontal sinuses, microstomia
-
-
+ Osteo-petrosis -
+
± acromial end
+
+
Normal
Average + Mild phthalmos Parrot-like
1q21
265800
Pycnodys ostosis
Delayed eruption & supra numerary Frontal & occipital bossing, narrow dropped shoulders
-
+ Normal Defective symphysis pubis -
+
±
++
-
Normal
Absent thumb, thin lips, pelvic dysplasia
Premature loss of teeth
-
-
Normal Hip dislocation
+
±
+
Partial alopecia +
Small
Average + Cataract
–
216340
Yunis-Varon
DM = Diabetes Mellitus
Average + Depressed bridge Broad base
6p21
119600
Cleido cranial
9:07
Stiff joints
Mandibular hypoplasia Clavical hypoplasia Acroosteolysis or acral defect Delayed closure of cranial sutures Wormian bone Bone density Pubic bone hypoplasia
Beaked/ pointed Partial alopecia
248370 (A) 608612 (B) 1q12.2 (A) 1p34 (B) Average + Prominent
Werner
Table II : Syndromes with overlapping manifestations to Mandibuloacral Dysplasia. HutchinsonGilford progeria 176670
20.10.2005
Scalp Hair
Nose
Gene map locus Birth weight Short stature Eyes
OMIM
Mandibulo acral dysplasia
5473_Genetic 4/2005 Page 360
GENETIC COUNSELING
5473_Genetic 4/2005
20.10.2005
9:07
Page 361
H.H. AFIFI ET AL., Mandibuloacral dysplasia
Recently, it has been discovered that point mutations in lamin A cause both disorders (4, 22). Therefore, it appears that different mutations in the same gene cause two different clinical diseases. Table II summarizes the clinical features of syndromes with overlapping manifestations to MAD. Werner syndrome can be differentiated from MAD by its later onset (after 20 years), and clinical features (7, 19), while acrogeria (Gottron type) by the absence of clavicle hypoplasia and visible veins (2, 25). Hallermann-Streiff syndrome has an earlier onset than MAD (9). The patients with cleidocranial dysplasia lack the facies and skin changes characteristic of MAD (8, 16). The various skeletal changes occurring with Hajdu-Cheney syndrome, Pycnodysostosis, and Yunis-Varon syndrome facilitate the differentiation from MAD (3, 13, 28). Studies on the distribution of body fat in patients with MAD have detected a specific fat distribution in patients with MAD type A or type B (10, 23, 24), while researches on glucose and lipid metabolism detected fasting and post-prandial hyperinsulinemia, together with elevated serum triglycerides and low cholesterol levels (5, 23). The specific body fat distribution and biochemical profile may be used as diagnostic tools for proving MAD in suspected patients. In summary, MAD is a genetically heterogenous disorder, associated with lipodystrophy, insulin resistance and its metabolic complications. Detecting the specific body fat distribution and biochemical profile in MAD patients, are reliable and easy methods to confirm the clinical diagnosis and to avoid misdiagnosis. Implementation of this strategy, may prove that MAD is not only a rare syndrome, but also an underdiagnosed disorder.
REFERENCES 1. AGARWAL A.K., FRYNS J.P., AUCHUS R.J., GARAG A. : Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum. Mol. Genet., 2003, 12, 1995-2001. 2. BLASZCZYK M., DEPAEPE A., NUYTINCK L., GLINSKA-FERES M., JABLONSKA S. : Acrogeria of Gottron type in a mother and a son. Europ. J. Dermatology, 2000, 10, 36-40. 3. BRENNAN A.M., PAULI R.M. : Hajdu-Cheney syndrome : evolution of phenotype and clinical problems. Am. J. Med. Genet., 2001, 100, 292-310. 4. CAO H., HEGELE R.A. : LMNA is mutated in Hutchinson-Gilford progeria but not in Wiedemann-Rautenstrauch progeroid syndrome. J. Hum. Genet., 2003, 48, 271-274. 5. CAUX F., DUBOSCLARD E., LASCOLS O., BUENDIA B., CHAZOUILLERES O., COHEN A., COURVALIN J.-C., LAROCHE L., CAPEAU J., VIGOUROUX C., CHRISTINMAITRE S. : A new clinical condition linked to a novel mutation on lamin A and C with generalized lipo-
6.
7.
8.
9. 10.
dystrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy. J. Clin. Endocrinol. Metab., 2003, 88, 1006-1013. CAVALLAZZI C., CREMONCINI R., QUADRI A.: Si du caso di disostosis cleido-cranica. Rev. Clin. Pediatr., 1960, 65, 313-326. CEFLE A., CEFLE K. : A case of mandibuloacral dysplasia presenting with features of scleroderma. Int. J. Clin. Pract., 2004, 58, 635-638. COGULU O., MUNANOGLU D., KARACA E., ONAY H., OZKINAY F. : Cleidocranial dysplasia with new additional findings. Genet. Counsel., 2004, 15, 229-231. COHEN M.M. JR. : Hallermann-Streiff syndrome : a review. Am. J. Med. Genet., 1991, 41, 488-499. CUTLER D.L., KAUFMANN S., FREIDENBERG G.R. : Insulin-resistant diabetes mellitus and hypermetabolism in mandibuloacral dysplasia : a newly recognized form of partial lipodystrophy. J. Clin. Endocrinol. Metab., 1991, 73, 1056-1061.
361
5473_Genetic 4/2005
20.10.2005
9:07
Page 362
GENETIC COUNSELING 11. ESTERLY N.B., BASELEGA E., DROLET B.A. : Familial mandibuloacral dysplasia. In: The Pigmentary System: Physiology and Pathology. J.J. Nordlung, R.E. Boissy, V.J. Hearing, R.A. King, J.P. Ortonne (eds). New York, Oxford University Press, 1998, 726-728. 12. GARG A. : Aquired and inherited lipodystrophies. N. Engl. J. Med., 2004, 350, 1220-1234. 13. GELB B.D., EDELSON J.G., DESNICK R.J. : Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping. Nature Genet., 1995, 10, 235-237. 14. HEGELE R.A. : Drawing the line in progeria syndromes. Lancet, 2003, 362, 416-417. 15. HOEFFEL J.C., MAINARD L., CHASTAGNER P., HOEFFEL C.C. : Mandibuloacral dysplasia. Skeletal Radiol., 2000, 29, 668-671. 16. MORAVA E., KARTESZI J., WEISENBACH J., CALIEBE A., MUNDLOS S., MEHES K. : Cleidocranial dysplasia with decreased bone density and biochemical findings of hypophosphatasia. Europ. J. Pediat., 2002, 161, 619627. 17. NG D., STRATAKIS C.A. : Premature adrenal cortical dysfunction in mandibuloacral dysplasia : a progeroid-like syndrome. Am. J. Med. Genet., 2000, 95, 293-295. 18 NOVELLI G., MUCHIR A., SANGIUOLO F., HELBLINGLECLERC A., D’APICE M.R., MASSART C., CAPON F., SBRACCIA P., FEDERICI M., LAURO R., TUDISCO C., PALLOTTA R., SCARANO G., DALLAPICCOLA B., MERLINI L., BONNE G. : Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am. J. Hum. Genet., 2002, 71, 426-431. 19. Online Mendelian Inheritance in Man, OMIM (TM). McKusick-Nathans Institue for Genetic Medicine, Johns Hopkins University (Baltimore, M.D.) and the National Center for Biotechnology Information, National Library of Medicine (Bethesda, M.D.) 2000. World Wide Web URL : http :// www.ncbi.nlm. nih.gov/omim/ 20. PRASAD P.V., PADMAVATHY L., SETHURAJAN S. : Familial mandibulo acral dysplasia a report of four cases. Int. J. Dermatol., 1998, 37, 614-616. 21. SCHRANDER-STUMPEL C., SPAEPEN A., FRYNS J.P., DUMON J. : A severe case of mandibuloacral dysplasia in a girl. Am. J. Med. Genet., 43, 877-881, 1992.
362
22. SHEN J.J., BROWN C.A., LUPSKI J.R., POTOCKI L. : Mandibuloacral dysplasia caused by homozygosity for the R527H mutation in lamin A/C. J. Med. Genet., 2003, 40, 854-857. 23. SIMHA V., AGARWAL A.K., ORAL E.A., FRYNS J.P., GARG A.: Genetic and phenotypic heterogeneity in patients with mandibuloacral dysplasia-associated lipodystrophy. J. Clin. Endocrinol. Metab., 2003, 88, 2821-2824. 24. SIMHA V., GARG A. : Body fat distribution and metabolic derangements in patients with familial partial liopdystrophy associated with mandibuloacral dysplasia. J. Clin. Endocrinol. Metab., 2002, 87, 776785. 25. TORIELLO H.V. : Mandibulo-acral dysplasia : heterogeneity versus variability. Clin. Dysmorphol., 1995, 4, 12-24. 26. TUDISCO C., CANEPA G., NOVELLI G., DALLAPICCOLA B. : Familial mandibuloacral dysplasia : report of an additional Italian patient. Am. J. Med. Genet., 2000, 94, 237-241. 27. VANTRAPPEN G., FEENSTRA L., MACOURS-VEREIST C., FRYNS J.P. : Mandibulo-acral dysplasia in a oneyear-old boy. Genet. Counsel., 2000, 11, 49-52. 28. WALCH E., SCHMIDT M., BRENNER R.E., EMONS D., DANE C., PONTZ B., WIESTLER O.D., BARTMANN P. : Yunis-Varon syndrome: evidence for lysosomal storage disease. Am. J. Med. Genet., 2000, 95, 157-160. 29. YOUNG L.W., RADEBAUGH J.F., RUBIN P., SENSENBRENNER J.A., FIORELLI G., MC-KUSICK V.A. : New syndrome manifested by mandibular hypoplasia, acroosteolysis, stiff joints and cutaneous atrophy (mandibuloacral dysplasia) in two unrelated boys. Birth Defects Orig. Art. Ser. VII, 1971, 7, 291-297.
ADDRESS FOR CORRESPONDENCE : Hanan Hosny Afifi Clinical Genetics Department National Research Centre El-Tahrir street, Dokki, Giza, Cairo, Egypt E-mail :
[email protected] Telephone : 202-7961821
