Turner s Syndrome - Current Approach. D Maji

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1 Turner s Syndrome - Current Approach D Maji Turner s Syndrome is a well recognized endocrine genetic disorder, characterized clinically by short stature; gonadal dysgenesis and some somatic anomalies; the typical karyotype is 45 XO. In 1938 H.H.Turner decribed 7 cases with sexual infantilism, congenital webbed neck and cubitas vulgus; Wilkinson & Heishman in 1944 established that underdeveloped ovaries were present in these cases i.e. the gonadal dysgenesis, a definitive evidence for X-chromosome abnormality was established in ,2 Today Turner s syndrome(ts) is a clinical challenge for its genetic, developmental, endocrine, cardiovascular, psychosocial and reproductive related problems. One in 2500 live female birth will have Turner s syndrome. 4,5 GENETICS AND TURNER S SYNDROME The karyotype 45XO is found in 1 to 2 % of all pregnancies of which 99% have spontaneous abortion. Less than 1% rare constitute the 1 in 2500 live female births who will have features of TS.Of all TS cases 50% will be 45XO karyotype, 25% will have mosaicism (e.g. 45XO/46XX) and rest will have structural abnormalities like 46XiXp, 46Xixq, 46XrX, 46XXpdel, 46XXqdel. 5 PRENATAL DIAGNOSIS Prenatal suspicion of TS is made when USG shows increased nuclear transluscency, presence of cystic hygromas, coarctation of aorta, brachycephaly renal anomalies, poly hydromnios or growth retardation. 6,7 Before terminating pregnancies in a suspected TS, a counseling should be done to the family explaining its broad clinical spectrum, possibility of short stature and management of ovarian failure and overall management protocol rather than giving a gloomy picture and a hurried decision of terminating the pregnancy. 8 Post natal diagnosis of TS is confirmed by karyotype test in all individuals with suspected TS. INDICATIONS FOR KARYOTYPING Unexplained growth failure Edema of hands and feet Left sided cardiac anomalies Phenotypic somatic features Short stature Delayed puberty Chronic otitis media Somatic Feature - The somatic feature which may be present in a case of TS are micrognathia, webbing of neck(30%); Coarctation of Aorta (15%) Bicuspid Aortic Valve, lymphoedema feet, epicanthal folds, low set ears, fish like mouth, high arched palate, short 4th metacarpal bone, cubitas vulgus, short neck, shield like chest, wide apart nipples, low hairline, curved nails, pigmented nevi. Clinical Features of 45X gonadal dysgenesis are shown in Table I. NEWBORN & TURNER S SYNDROME Any newborn with Turner s Syndrome, it is the responsibility of the Pediatrician to identify cardiovascular abnormalities if any, to plan for the treatment of short stature; to consult otolaryngologist if hearing and speech difficulties are found. Timely initiation of puberty is also an important decision to make.

2 192 Medicine Update-2011 Table I. Clinical Features of 45X gonadal dysgenesis Karyotype Inheritance Gonads Wolfian duet derivatives Mullerian derivatives External genitalia Habitus 45XO Sporadic, meiotic or mitotic nondysjunction Streak Absent normal female Female short stature, sexual infantilism at puberty, somatic stigmata Hormone profile LH FSH E 2 LH- Leutinising Hormone, FSH- Fallicular Stimulating Hormone, E 2 17-B estradial TURNER S SYNDROME AND CARDIOVASCULAR SYSTEM (CVS) There is very high fetal mortality in the newborn TS because of the defect in cardiac and aortic development. The affected fetus demonstrate obstructed jugular lymphatics with nucheal cystic hygromas.the fetal cystic hygromas compress outflow tracts leading to cardiovascular defects. These lymphatics are found in all who don t survive. Those who survive have peripheral lymphaedema and webbing of neck which regress by the age of 2 yr. A residual post natal webbing of neck may predict Bicuspid Aortic valve or Coarctation of Aorta. Bicuspid Aortic valve may clinically remain silent in childhood with a risk of endocarditis. Later clinically significant Aortic Stenosis or Aortic Regurgitation develop which may lead to ascending aorta dilatation and aneurysm formation and later dissection of aorta 9.10,11. A paedeiatric cardiologist should have a throrough clinical examination before doing an ECG and Doppler Echocardiography, if needed a cardiac MRI may be planned. Even there is no CVS anomaly, blood pressure should be monitored and reassessment to be done in later childhood. If a child has CVS anomaly, prophylaxis for endocarditis, monitoring aortic dilatation and control of blood pressure is in the protocol of management. Re-evaluation to be done every year. ECG may show Right axis deviation. T wave changes,accelerated AV conduction and QTc prolongation. Impaired vagal tone is associated with unusual resting tachycardia. Risk for aortic dissection is always there with Bicospid Aortic valve, Coaractation of Aorta, Dilatation of Aorta and Hypertension. Hypertension is the most important treatable factor. ORTHDONTICS & TS All TS patients should consult a pediatric orthodontist by 7 yrs of age for some distinct craniofacial features which are associated with TS 12. They are as follows:- Craniofacial features of TS. Flattened cranial base angle Narrow maxilla with high arched palate Wide mandible with micrognathia Early eruption of secondary tooth Short roots- tooth loss URINARY SYSTEM & TS TS may be associated with some congenital malformation of urinary system e.g. collecting system malformation. Horse Shoe kidney, malrotation. 13 They are more prone to develop hypertension and urinary tract infection. An ultrasonography of KUB region is advised. EAR AND TS Abnormal cranial bone anatomy, abnormal relationship between Eustachian tube and middle ear; leads to otitis media and conductive hearing loss. Otoscopic examination and tympanometry done by ENT specialist to confirm diagnosis. Aggressive therapy may be needed in some cases which may include tympanostomy tube placement. Audiological survillance is done every one to three years. In adulthood, progressive sensorineural hearing loss with dip in the 1.5 to 2 k Hc region may neccessiate hearing aids 14. AUTOIMMUNITY AND TS Increased risk of autoimmune thyroiditis and coeliac disease has been noted with TS. 24% of TS subjects develop hypothyroidism. Anti TPO antibody identifies high risk patients. All TS patients should be screened annually for TSH. 15 SHORT STATURE and TS Short stature is a readily recognizable clinical feature in Turner s Syndrome. In female short subjects, TS is an important differential diagnosis. The terminal short arm of X chromosome and pseudoautosomal region contain two important genes for linear growth, PHOG (Pseudoautosomal homeobox containing osteogenic gene) and SHOX (Short Stature homeobox containing gene). These growth promoting genetic materials are lost as a result of translocation; lending to short stature is TS 16,17. The growth pattern of TS are as follows. Growth pattern is TS Mild IUGR (Intraintranterian growth rate). Slow growth in infancy.

3 Medicine Update Delayed onsent of childhood component of growth. Growth failure in childhood. Absence of pubertal growth To an endocrinologist, the objective of growth promoting treatment in TS is, i) to attain a normal height for age; ii) puberty at normal age; and iii) attain a normal adult height inspite of having a normal growth hormone pattern; Growth hormone(gh) therapy increases a growth velocity and final height if treated at proper time. It requires a higher dose of GH i.e. 0.3 mg/kg/bwt./wk. Growth hormone is effective from 9 month age and most effective in cases with taller height at initiation of treatment, tall parental height, younger age of initiation of treatment, long duration if therapy and high growth hormone dose. GH therapy should be tried until a satisfactory height is attained and until little growth potential remains (bone age < 14 yrs) SEXUAL INFANTILISM AND TS Normal pubertal development and spontaneous menstruation do not occur in general in cases of TS. 20 In fact absent pubertal development is one of the most common clinical presentation in our country. Very few, particularly those who are Mosaic(e.g. 46XX/45XO) may have some pubertal development, and rarely have menarche and even pregnancy (if these individuals marry at early age).clinical pubertal assessment is a must in TS who is above 11 yr age. Staging of puberty should be noted before the treatment for puberty induction. Timing of puberty is extremely important and it should conform with the peers. Previous recommendation was to delay until 15 year to optimize height potential, but now the approach is totally different. Present recommendation is to start treatment to induce puberty by the age 12, especially for the bone and psychosocial health. 21 Estradial is the preferred form of Estrogen which may be given orally, transdermally or by injectable form 22.Estrogen only should be given and addition of progestin to be delayed for at least 2 yrs. Use of oral contraceptive pills to be avoided because it contains synthetic high dose of Estrogen and synthetic progesterone interferes with optimal breast and uterine development. PUBERTY INDUCTION IN TS Dosing Oral Estradial 2mg/D Transdermal do 0.1 mg/d Injectable do 2.5 mg/month PSYCHOSOCIAL FUNCTION AND TS Ovarian failure leads to delayed sexual development and higher level of shyness which may lead to social anxiety and reduced self esteem, this is further aggravated if they are married and have infertility. Contrary to the previous belief, majority of TS subject have normal intelligence with good verbal skills and have normal education even upto university level. Estrogen replacement therapy improves quality of life and should be continued till the age of menopause. Osteoporosis and fracture risk is high in TS women not taking oestrogen. Estrogen therapy maintains feminization and prevents osteoporosis 23, 24. Turner s Syndrome at VIMS ( ) are shown in Table II. OVARIAN REPLACEMENT AND TS AGE(Yrs) Suggestion Monitor for spontaneous puberty Start low dose E Gradually increase E 2 dose Begin cyclical progesterone Continue full dose E Lowest E 2 to prevent osteoporosis >50 Same as other post-menopausal women INFERTILITY AND TS Struggling with their infertility is the greatest challenge they face in adapting to a life with TS. Oogonia found in fetal life, do not develop to Oocyte in TS, so majority remain sterile with permanent amenorrhea. Rarely a mozaic Turner may have functional ovaries, but run the risk of premature ovarian failure. In such cases pregnancy should not be postponed. Majority TS are without functional ovaries. Appropriate preparation of uterus to be done with estrogen, so that to get a thickness of endometrium of at least 7mm. After that pregnancy may be tried with Oocyte or a embryo donation. Increased maternal complication are with short stature, hypertension, and dissection of aorta. Subjects with a bicuspid valve, dilated aorta and coaractation are best counseled against pregnancy. 25 CONCLUSION Short stature, somatic anomalies, gonadal dysgenesis with a karyotype of 45XO are the cardinal features of Turner Syndrome. Newborn screening; cardiovascular Echo; growth hormone treatment, appropriate pubertal development and a multidisciplinary care has changed the total approach to Turner syndrome cases with a hope to give a normal quality

4 194 Medicine Update-2011 Table II. Turner s Syndrome at VIMS ( ) VIMS - Vivekananda Institute of Medical Sciences, Kolkata of life to them. Parents receiving prenatal diagnosis be informed of broad clinical spectrum of TS and good quality of life. Puberty should not be delayed. Cardiovascular screening, comprehensive evaluation in childhood, growth hormone treatment to gain stature; monitoring hearing and thyroid function; monitoring blood pressure, cardiac anomalies, proper education could lead to normal fruitful life in TS. Pregnancy and family possible with proper uterine preparation and ovum donation. REFERENCES 1. Nielsen J, Wohlert M 1991 Chromosome abnormalities found among 34,910 newborn children: results from a 13 year incidence study in Arhus, Denmark Hum Genet 87: Turner HH 1938 A syndrome of infanitilism,congenital webbed neck, and cubitus valgus. Endocrinology 23: Gravholt CH, Juul S, Naeraa RW, Hansen J 1996 Prenatal and postnatal prevalence of Turner s syndrome: a registry study. BMI 312: Baena N, De Vigan C, Cariati E, Clementi M, Stoll C, Caballin MR, Guitart M 2004 Turner syndrome:evaluation of prenatal diagnosis in 19 European registries. AM J Med. Genet A 129: Hook EB, Warburton D 1983 The distribution of chromosomal genotypes associated with Turner s syndrome : liverbirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosalisism. Hum Genet 64: Surerus E, Huggon IC, Allan LD 2004 Turner s syndrome in fetal life. Ultrasound Obstet Gynecol 22: Miyabara S, Nakayama M, Suzumori K,l Yonemitsu N, Sugihara H 1997 Developmental analysis of cardiovascular system of 45,X fetuses with cystic hygroma. AM J Med Genet 68: Hamamy Ham, Dahoun S 2004 Parental decisions following the prenatal diagnosis of sex chromosome abnormalies. Eur J Obstet Gynecol Reprod Biol 116: Loscalzo MK, Van PL, Ho VB, Bakalov VK, Rosing DR, Malone CA, Dietz HC, Bondy CA 2005 Association between fetal lymphedema and congenital cardiovascular defects in Turner syndrome. Pediatrics 115: Sybert VP 1998 cardiovascular malformations and complications in Turner syndrome. Pediatrics 101:E Lin AE, Lippe B, Rosenfeld RG 1998 Further delineation of aortic dilation, dissection, and rupture in patients with Turner syndrome. Pediatrics 102:E Lippe B 1991 Turner syndrome. Endocrinol Metab Clin North AM 20: Chang P, Tsau YK, Tsai WY, Tsai WS, Hou JW, Hsiao PH, LEE KS 2000 Renal malformations in children with Turner s syndrome J formos Med Assoc 99: Dhooge IJ, De Vel E, Verhoye C, Lemmerling M, Vinck B 2005 Otologic disease in Turner syndrome. Otol Neurotol 26: El-Mansoury M, Bryman I, Berntorp K, Hanson C, wilhelmsen L, Landin Withelmsen K 2005 Hypothyroidism is common in Turner syndrome : results of a five-year follow-up. J.Clin Endocrinol Metab 90: Lyon AJ, Preece MA, Grant DB 1985 Growth curve for girls with Turner

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