Genetic Evaluation of Proportionate Short Stature in Alexandria, Egypt

original article Egypt. J. Med. Hum. Genet. Vol. 9, No. 2, Nov. 2008 Genetic evaluation of proportionate short stature in Alexandria, Egypt

Amal Kotb Behery

Human Genetics Department, Medical Research Institute, Alexandria University

ABSTRACT

Introduction: Compared with a genetically relevant population, short stature (ss) is defined as a standing height more than 2 standard deviations below the mean (or below the third percentile) for gender. SS is a common problem for children and adolescents worldwide. The Aim: This study was conducted to reveal the spectrum of the genetic causes of proportionate ss in Alexandria, Egypt. Patients and Methods: A total of 120 patients with proportionate SS, (87 girls and 33 males), ages ranging from 6 months to 15 years, selected from the Human Genetic Clinic, Medical Research Institute, Alexandria University, Egypt, were included in this study. All patients were subjected to detailed genetic and family history, clinical genetic examination with particular attention to body proportions and dysmorphic features, anthropometric measurments, radiological examination and chromosomal analysis. Results: Parental consanguinity was found among 60.4% of the patients. About 37.5% of the cases had positive family history of short stature. It was found that proportionate SS was due to pathologic causes in 87.5% of the cases and to normal growth variants as constitutional growth delay and familial short stature in 12.5% of the cases. Pathologic causes included fetal malformation syndromes (27.2%), genetically determined systemic diseases (23.3%), chromosomal abnormalities (20%), and endocrine disorders (17.6%). About 25% of the studied girls had Turner syndrome. Accurate diagnosis of SS modifies the management plan for the patient and allows psychological and genetic counseling for the family. Karyotype analysis is recommended for all girls with unexplained SS. A sensitive screening system and an effective referral channel to genetic centers are especially important in the management of SS.

Key Words: Corresponding Author: Short stature, genetic etiology, malfor- Dr: Amal Kotb Behery mation syndromes, chromosomal dis- E-mail: [email protected] orders.

Adequate lengthening of the skeleton is because the underlying medical condi- influenced by genetic, nutritional, envi- tions must be detected and treated be- ronmental and hormonal factors1 Short fore fusion of the epiphysis.2,5 stature (SS), optimally defined relative to the genetic endowment of the indi- Accurate diagnosis of SS modifies the vidual, is recognized by comparing an management plan for the patient and in- individual child’s height with that of dicates psychological as well as genetic a large population of a similar genetic counseling for the family1,3. This study background and, more particularly, us- was conducted to reveal the spectrum ing the mid-parental target height. of the genetic causes of proportionate SS in Alexandria, Egypt. Regardless of the genetic background, SS may be a sign of a wide variety of PATIENTS AND METHODS pathologic conditions or inherited disorders. Thus accurate longitudinal growth This study included 120 patients with assessment is a fundamental aspect of proportionate short stature (87 females health maintenance in children.1,2 and 33 males). Ages ranged from 6 months to 15 years. They were selected Short stature (SS) is defined as supine from the Human Genetic Clinic, Medi- length for children under three years cal Research Institute, Alexandria Uni- old, or standing height for older chil- versity, Egypt. dren, to be below the third percentile or two standard deviations from the mean All patients were subjected to detailed height for age of a genetically relevant genetic and family history; including population2,3. The prevalence of SS is the child’s weight and length at birth, about 3% world wide.4 the final heights, weights and pubertal timing in the parents and siblings; with Short stature may be proportionate or pedigree construction. Clinical genetic disproportionate according to the body examination with particular attention to habitus. Children with disproportion- body proportions, dysmorphic features, ate SS usually have a skeletal dysplasia midline defects, and systems review for while those with proportionate SS may chronic illness. Anthropometric mea- have a more generalized disorder.1,2,5 surements were carried out according to Tanner et al.6 The standing height in The causes of proportionate SS are het- children or recumbent length in infants, erogenous ranging from genetic patho- was determined and plotted on Egyptian logical causes to normal growth variants control chart7. In cases, who can’t com- such as familial SS and constitutional pletely stand or recline (e.g. those with delay in growth and maturation. Path- spina bifida and/or contractures) arm ological causes include systemic dis- span provides a reliable alternative for ease, endocrine disorder, psychological longitudinal assessment of long bone dwarfism, genetic syndrome or a chro- growth. Head circumference and weight mosomal or a teratogenic disorder.4,5 measurement are essential. Arm span to height ratio (around 1.0 at all ages), to- Short stature should not be overlooked gether with sitting height to lower body 172 Amal Kotb Behery segment (in newborn around 1.7, which phatemic rickets were diagnosed early gradually drops to approximately 1 by because of a positive family history, 10-12 years and remains just below 1.0 hypophosphatemia and elevated serum in adulthood) are important to confirm alkaline phosphatase with normocalce- the diagnose of proportionate SS.2 mia.

Radiological examination (including Twenty four cases (20%) had chromo- skeletal survey and bone age examina- somal abnormalities (22 females and 2 tion), and chromosomal analysis using males). All females cases had Turner G-banding technique were done8. Other syndrome, i.e. 25.3% (22/87) of the investigations were performed when studied females had Turner syndrome indicated to confirm diagnosis e.g. hor- (either classical, variant or mosaic). monal assay, urine screening, Hb elec- The most frequent karyotype was 45, trophoresis, ultrasonography, ECHO X detected in 10 cases. Other cases had and CT scan. mosaicism and structural abnormalities of the X-chromosome. Two males RESULTS had chromosomal aberrations; one had 47, XXY and GHD, the other had de- This study included 120 patients (87 letion of short arm of chromosome 18 females and 33 males) with proportion- with panhypopituitarism. (Tables 1,3). ate short stature. Ages ranged from 6 Increased chromosomal breaks was de- months to 15 years. The female to male tected in patients with fanconi anemia, ratio was 2.6:1. and defective DNA repair after UV exposure was demonstrated in patients The studied cases were classified -ac with De-Sanctis Cacchione syndrome. cording to the genetic etiology into; pathological SS (105 cases) and normal Twenty cases (16.7%) had endocrine growth variants (15 cases)(Table 1). disorders. Ten had growth hormone deficiency [Isolated GHD (8) and pan- For the group with pathological causes hypopituitarism (2)], three had GH of proportionate SS, 33 cases (27.5%) insensitivity syndrome and seven had had syndromal disorders. [19 autosom- congenital hypothyroidism. al dominant, 12 autosomal recessive, 2X-L dominant]. The most frequent Fifteen cases (12.5%) had normal were Russell-Silver, Noonan and Seck- growth variants; 8 had constitutional el syndrome (Tables 1,2). growth delay and 7 had familial short stature (Table 1). Twenty eight cases (23.3%) had systemic diseases; 16 had mucopolysacha- In the present study 37.5% of the cases ridosis, 10 had haemoglobinopathies had positive family history of propor- (7β thalassemia and 3 seckle cell ane- tionate SS. The frequency of parental mia) and 2 had hypophosphatemic rick- consanguinity was 60.4% (Table 4). ets. (Table 1). Patients with hypophos-

173 Genetic evaluation of proportionate short stature in Alexandria, Egypt Table 1: Classification of the studied cases according to their genetic etiology. Genetic etiology No %

I. Pathologic causes <<105>> • Syndromal disorders 33 27.5

• Systemic diseases [28] 23.3

- Mucopolysaccharidosis 16

- Haemoglobinopathies 10

- X-L hypophosphatemic rickets 2

• Chromosomal disorders 24 20

• Endocrine disorders [20] 16.7

- Growth hormone deficiency 10

- GH insensitivity syndrome 3

- Congenital hypothyroidism 7

II. Normal growth variants <<15>> 12.5 - Constitutional growth delay 8 - Familial short stature 7 Total 120 100

Table 2: Distribution of cases with syndromal disorders. Single gene disorder No MIM(9)* Autosomal dominant [19] - Russell-Silver syndrome 7 *180 860 - Noonan syndrome 5 163 950 - Neurofibromatosis type 1 3 162 200 - Rubinstein-Taybi syndrome 2 180 849 - Cornelia-de lange syndrome 2 122 470 Autosomal recessive [12] 12.5 - Seckel syndrome 4 **210 600 - De-Sanctis-cacchione syndrome 2 278 800 - Wolfram syndrome [DIDMOAD] 2 222 300 - Fanconi anemia 2 227650 - Robinow syndrome 2 268 310 X-linked dominant [2] - Focal dermal hypoplasia 2 ***305600 Total 33 * MIM: Mckusick Inheritance in Man. * Autosomal dominant [AD]. ** Autosomal recessive [AR]. *** X-linked dominant [X-L]. 174 Amal Kotb Behery Table 3: Distribution of cases according to In the present study, the female to male their cytogenetic results. ratio was 2.6:1. Previous studies re- 10,11 Karyotype No ported similar findings this is due to the high index of suspicious of Turner Normal female 65 syndrome and the awareness of the im- Abnormal female [Turner] (n=22) portance of its early recognition and - 45,X 10 treatment. - 46,X,i(X ) 4 q In the present study, 105 (87.5%) cases - 46,XX/45,X 3 had genetic pathological conditions and - 46,X,del (X ) 2 p 15 (12.5%) had normal growth vari- - 46,XX/46,X,i(Xq) /45,X 2 ants. Several previous studies reported - 45,X/46,X,r(X) 1 a higher frequency of normal growth 1,12 Normal male 31 variants ranging from 32% to 47%. The high frequency of genetic patho- Abnormal male [n=2] logical conditions in the present study - 47,XXY 1 is due to the fact that most of the re- - 46,XY,del(18)(P ) 1 11 ferred cases to our genetic unit had ge- Total 120 netic and/or inherited disorders.

There is a wide variety of fetal malfor- Table 4: Distribution of cases according to mation syndromes associated with pro- parental consanguinity and family history. portionate SS, caused by single gene Family history Parental disorders. Although in most cases, the of SS consanguinity Type causes are obscure, a specific diagnosis No % No % of a recognizable syndrome usually can be made.5 Positive 36 37.5 58 60.4 Negative 60 62.5 38 39.6 Previous studies reported syndromal Total *96 100 96 100 disorders as an important cause of pathologic SS2,5. In the present study, Total number after exclusion of chromosomal sydnromal disorders were diagnosed anomalies (24 cases). in 33 cases. The most frequent were Russell-Silver syndrome. Noonan Syn- drome and Seckel syndrome. This is in DISCUSSION agreement with previous studies.4,10

Short stature is a common problem for Many fetal malformation syndromes children and adolescents worldwide. It with proportionate SS are inherited as may be a disability and a cause of dis- autosomal recessive traits5. In this study, tress in itself. Therefore, SS is important 12 cases had AR syndromes [Seckel and require early assessment2,9. A sensi- syndrome, De-sanctis Cacchione syn- tive screening system and an effective drome, Wolfram syndrome, Fanconi referral channel to genetic centers are anemia and Robinow syndrome]. The specially important in the management presence of affected sibs together with of SS.9 parental consanguinity in eight cases

175 Genetic evaluation of proportionate short stature in Alexandria, Egypt supported AR inheritance. Robinow ment plan for the patient and indicates syndrome is genetically heterogenous psychological and genetic counseling condition. The detection of rib fusions for the family5,10. Growth hormone in the studied cases confirm the diagno- therapy in children with some malfor- sis of autosomal recessive variant.13 mation syndromes e.g. Russell-Silver Syndrome and Noonan Syndrome im- In the present study, increased chromo- proves final height.16,18,20 somal breaks was detected in 2 cases with Fanconi anemia, and defective Many previous studies reported sys- DNA repair after UV exposure was temic diseases as a pathologic cause demonstrated in another 2 cases with of SS2,3 Sixteen cases in this study had De-Sanctis Cacchione Syndrome. This mucopolysaccharidosis. (MPS). Short confirmed their diagnosis. This is previ- stature in MPS is most probably due to ously reported.14,15 growth hormone deficiency, low insulin-like growth factor-1 and/or hypo- Other fetal malformation syndromes thyroidism21. Enzyme replacement and with proportionate SS usually occur hematopioetic stem cell transplantation sporadically such as Russell-Silver are used to treat children with MPS.21,22 Syndrome, Cornelia de-lange syndrome and Rubinstein-Taybi syndrome, due to Short stature is a frequent clinical pic- new mutation or submicroscopic chro- ture in haemoglobinopathices most mosomal deletion5,16. In this study, 11 probably due to dysfunction of growth cases had Russell-Silver, Conelia de- hormone-insulin like growth factor-I lange and Rubinstein-Taybi syndrome. axis23,24. In the present study, 7 patients Negative family history in all these cas- had thalassemia major and 3 had sickle es suggests new mutation. cell anemia. Recombinant growth hormone therapy improves growth velocity, Some malformation syndromes with heart function and bone mineral density proportionate SS are inherited as auto- in thalassemic patients23. Two studied somal dominant trait5. In this study, 3 cases had X-L hypophosphatemic rick- cases had neurofibromatosis type I and ets. X-L hypophosphatemic patients 5 cases had Noonan Syndrome. This present with disproportionate SS and has been previously reported17,18. Care- bone deformities of the lower limbs25. ful clinical examination of their parents The cases detected in this study were revealed affected parents in 4 cases, early diagnosed, before development of confirming AD inheritance, necessi- bone deformities, because of the pres- tating genetic counseling and prenatal ence of similarly affected sibs. Treat- diagnosis. Two studied cases had fo- ment with Vit D metabolites combined cal dermal hypoplasia, which is an X-L with inorganic phosphate salts improve dominant trait19. An effective multidis- linear growth as well as healing rickets ciplinary intervention can improve the in some patients.25 quality of life in these cases. In the present study, 24 cases (20%) Although, most autosomal abnormali- had chromosomal anomalies. Turner ties and syndromal disorders are not syndrome represented 25.3% (22/87) of treatable in terms of final height, a de- the studied females. The most frequent finitive diagnosis modifies the manage- Karyotype was 45, X detected in 10 cas- 176 Amal Kotb Behery es, other cases had mosaicim and struc- appropriate as GH replacement is nec- turial abnormalities of the X-chromo- essary. Congenital hypothyroidism is some. Previous studies revealed similar one of the most common preventable findings10,11,26 some girls with Turner causes of mental retardation32. In the syndrome especially those with mosa- present study, 7 cases had congenital icism express few phenotypic features hypothyroidism, four of them had pa- prepubertally except for SS. Therefore, rental consanguinity and affected sibs. all girls with unexplained SS have to This is most probably due to an auto- be referred for genetic evaluation and somal recessive inborn error in thyroid chromosomal studies. In Turner syn- hormone synthesis. Newborn screening drome, introducing growth hormone for programme is important to allow early SS in early childhood and osterogen by detection and treatment.32 adolescence for pubertal development and prevention of osteoporosis is very In the present study, normal growth important.27,28 variants were diagnosed in 15 cases (8 had constitutional growth delay and 7 In the present study, 2 males had chro- had familial SS). All had positive fam- mosomal anomalies. Moreno-Garcia ily history of SS and/or delayed pu- et al reported a low frequency of chro- berty. In adolescent with constitutional mosomal anomalies among males with growth delay, and severe psychological SS11. One male had Klinfelter syndrome distress, hormone therapy to accelerate and growth hormone deficiency. This is puberty may be appropriate33. Careful previously reported by Reinehr et al.29 clinical examination of parents in cases The other male had deletion of short suggestive of familial SS is very impor- arm of chromosome 18 together with tant because some of the pathological panhypopituitarism. This chromosomal causes of SS are inheritable. anamoly was previously reported with a single maxillary incisor suggesting that In the present study, 60.4% of the cas- the associated pituitary insufficiency es had consanguineous parents, which may be due to hypothalamic defects5. is higher than the general population This indicates the needs for cytogenetic (28.9%)34. The association of parental study in all children with proportionate consanguinity and genetic disorders SS. was proved in previous studies1,35. This could explain the presence of different Many disturbances in the endocrine inheritable disorders with proportionate system can impair linear growth1,2. In SS in this study. Genetic counseling is the present study. Twenty cases (16.7%) highly recommended in these families. had endocrine disorders. The common- est was growth hormone deficiency CONCLUSION (GHD). This is in agreement with previous studies1,3,30. In the present study, 10 This study highlighted the genetic eti- cases had GHD [8 had isolated GHD, 2 ologies of proportionate SS. Syndromal had panhypopituitarism] and 3 had GH disorders, systemic diseases and chro- resistance syndrome. The basic defect mosomal disorders are the most fre- in GH resistance syndrome is abnormal quent genetic causes of proportionate or deficient GH receptors31. Referral SS in Alexandria, Egypt. 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