Gender Issues and Related Social Stigma Affecting Patients with a Disorder of Sex Development in India.

Children with disorders of sex development (DSD) manifest at birth with malformed genitalia or later with atypical pubertal development. Those born with malformed genitalia are often diagnosed at birth. However, in resource-poor countries like India, where not all births are supervised by healthcare workers, some of these children remain undiagnosed until puberty or even later. The aim of this study was to assess the gender issues and psychosocial problems of children with DSD. Participants included 205 children with DSD (103 with 46,XX DSD and 102 with 46,XY DSD). Both the children with DSD and their parents underwent semistructured interviews by a clinical psychologist. The birth of a child with DSD was perceived as a major medical and social problem by parents from all socioeconomic strata. Mothers were distressed as many believed the DSD condition was transmitted through the mother. Children who were not diagnosed and treated during infancy or early childhood experienced considerable social discrimination not only from relatives and friends but also from medical and paramedical staff in hospitals. Several patients had been operated during infancy without an etiological diagnosis and without provision of adequate information to the parents. Some children had problems related to complications of surgery. Most teenage patients with 5α-reductase-2 deficiency reared as females presented with gender dysphoria, while children with androgen insensitivity (except for one) or with gonadal dysgenesis developed a gender identity concordant with their gender of rearing. Parents of children with DSD preferred a male gender assignment for their children (if that was possible) because of the social advantages of growing up male in a patriarchal society.

Effect of Different Insulin Response Patterns During Oral Glucose Tolerance Test on Glycemia in Individuals with Normal Glucose Tolerance.

BACKGROUND: Research is still going on for detecting the earliest glucose homeostasis derangements in individuals, which is crucial for the prevention of glucose intolerance. This cross-sectional study analyzes different insulin response patterns during the oral glucose tolerance test (OGTT) and their implications on glycemia in normoglycemic individuals. SUBJECTS AND METHODS: The sample frame was the "Offspring of Individuals with Diabetes Study" database. All participants underwent OGTT. Blood samples were collected at 0, 30, 60, and 120 min for measurement of insulin, C-peptide, and proinsulin levels. Normal glucose tolerant individuals were selected for analysis. RESULTS: Four hundred fifty subjects (mean age, 25 years) were included and divided into two groups according to timing of plasma insulin peaking during OGTT: Group 1, peaking at 30 min; and Group 2, peaking at 60 or 120 min. Body mass index (BMI) and insulin resistance were comparable between the groups; however, Group 2 showed a significantly higher 60- and 120-min glucose level and lower disposition index. Based on the magnitude of the insulin levels, Group 1 was subdivided into Group N (normal pattern) and Group E (exaggerated pattern) with a 30-min insulin cutoff of 74 µU/mL (Group E, ≥74 µU/mL). Group 2 was subdivided into Group DL (delayed and limited pattern; 60-min insulin <73.0 µU/mL and 120-min insulin <80.0 µU/mL) and Group DE (delayed and exaggerated pattern; 60-min insulin ≥73.0 µU/mL or 120-min insulin ≥80.0 µU/mL). Group DE showed a significantly higher area under the curve (AUC) of glucose compared with the other groups and had a lower disposition index and high-density lipoprotein levels. Group DL had significantly lower insulin resistance and BMI compared with Group E but showed a similar AUC of glucose. CONCLUSIONS: A delayed insulin pattern was associated with higher postprandial glucose levels. Individuals with delayed and exaggerated insulin secretion may have a higher risk for glucose intolerance.

Accuracy of 68Ga DOTANOC PET/CT Imaging in Patients With Multiple Endocrine Neoplasia Syndromes.

OBJECTIVE: The aim of this study was to evaluate the role of 68Ga DOTANOC PET/CT imaging in patients with multiple endocrine neoplasia (MEN) syndromes. PATIENTS AND METHODS: Data of 33 patients (age, 33.5 [13.8] years; male 14/female 19) with MEN syndromes (MEN 1, 9; MEN 2A, 19; MEN 2B, 5) who underwent 41 68Ga DOTANOC PET/CT studies were retrospectively analyzed. Twenty PET/CTs were done for staging and 21 for restating. PET/CT images were evaluated in consensus by 2 nuclear medicine physicians, qualitatively and semiquantitatively (SUV(max)). A combination of histopathology, clinical, and biomarker follow-up was taken as reference standard. RESULTS: Of the total 41 68Ga DOTANOC PET/CTs, 34 were interpreted as positive for neuroendocrine tumors (NETs) and 7 as negative. The patientwise sensitivity of PET/CT was 94% (95% confidence interval [CI], 80-99), specificity was 71% (95% CI, 29-96), positive predictive value was 94% (95% CI, 80-99), negative predictive value was 71% (95% CI, 29-96), and accuracy was 90%. A total of 74 disease sites were demonstrated on PET/CT, including 41 primary NETs (pancreas, 10; stomach, 2; pheochromocytoma, 10; medullary thyroid carcinoma, 19), 31 metastatic sites (lymph node, 15; liver, 10; bone, 4; lung, 1; breast, 1), and 2 parathyroid adenomas. Lesionwise sensitivity, positive predictive value, and accuracy of PET/CT were 93%, 96%, and 90% overall, 89%, 95%, and 85% for primary tumors, and 100%, 97%, and 97% for metastasis, respectively. Among primary tumors, the SUV(max) of medullary thyroid carcinoma was significantly lower than gastro pancreatic NETs (P = 0.003) and pheochromocytomas (P = 0.003). No site-specific difference was seen in SUV(max) of metastatic lesions. CONCLUSIONS: 68Ga DOTANOC PET/CT shows high diagnostic accuracy in MEN syndrome and can demonstrate both primary and metastatic NETs in these patients.

Evaluation of (68)Ga-DOTANOC PET/CT imaging in a large exclusive population of pancreatic neuroendocrine tumors.

PURPOSE: To evaluate the diagnostic accuracy of (68)Ga-DOTANOC PET/CT imaging in a large exclusive population of pancreatic neuroendocrine tumors (NETs). METHODS: Data of 141 (mean age 46.2 ± 15.2 years) patients who underwent 178 (68)Ga-DOTANOC PET/CT studies for diagnosis/staging (n = 88) and restaging (n = 90) of pancreatic NET were retrospectively analyzed. PET/CT results were compared to conventional imaging (CIM) when available (n = 86). Histopathology and/or clinical/imaging follow-up (minimum 6 months) were used as reference standard. RESULTS: The overall sensitivity, specificity, and accuracy of (68)Ga-DOTANOC PET/CT were 85.7%, 79.1%, and 84.8%. The corresponding values were 73%, 50%, and 70.4% for diagnosis/staging groups and 98.6%, 100%, and 98.8% for restaging groups. The accuracy was significantly higher for restaging as compared to diagnosis/staging (P < 0.0001) and in non-insulinoma tumors than insulinomas (P < 0.0001). The SUVmax of primary tumors was significantly higher than metastatic lesions overall (P = 0.001), as well as in diagnosis/staging (P = 0.041) and restaging (P = 0.0003) subgroups. When available, CIM was less specific than (68)Ga-DOTANOC PET/CT (P < 0.001) and showed fewer lesions. CONCLUSIONS: (68)Ga-DOTANOC PET/CT is useful for diagnosis/staging and restaging of patients with pancreatic NET. It demonstrates more lesions compared to CIM and is more specific.

Comparison of the prognostic values of 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT in patients with well-differentiated neuroendocrine tumor.

PURPOSE: To determine the prognostic value of (68)Ga-DOTANOC PET/CT in patients with well-differentiated neuroendocrine tumor (NET), and to compare the prognostic value with that of (18)F-FDG PET/CT and other conventional clinicopathological prognostic factors. METHODS: Data from 37 consecutive patients (age 46.6 ± 13.5 years, 51% men) with well-differentiated NET who underwent (68)Ga-DOTANOC PET/CT and (18)F-FDG PET/CT were analyzed. All patients underwent a baseline visit with laboratory and radiological examinations. Clinical and imaging follow-up was performed in all patients. Progression-free survival (PFS) was measured from the date of the first PET/CT scan to the first documentation of progression of disease. RESULTS: (68)Ga-DOTANOC PET/CT was positive in 37 of the 37 patients and (18)F-FDG PET/CT was positive in 21. During follow-up 10 patients (27%) showed progression of disease and 27 (73%) showed no progression (24 stable disease, 3 partial response). The median follow-up was 25 months (range 2 - 52 months). Among the variables evaluated none was significantly different between the progressive disease and nonprogressive disease groups, with only SUVmax on (68)Ga-DOTANOC PET/CT being borderline significant (P = 0.073). In the univariate analysis for PFS outcome, SUVmax on (68)Ga-DOTANOC PET/CT (HR 0.122, 95% CI 0.019 - 0.779; P = 0.026) and histopathological tumor grade (HR 4.238, 95% CI 1.058 - 16.976; P = 0.041) were found to be associated with PFS. Other factors including age, sex, primary site, Ki-67 index, TNM stage, (18)F-FDG PET/CT status (positive/negative), SUVmax on (18)F-FDG PET/CT and type of treatment were not significant. In multivariable analysis, only SUVmax on (68)Ga-DOTANOC PET/CT was found to be an independent positive predictor of PFS (HR 0.122, 95% CI 0.019 - 0.779; P = 0.026). CONCLUSION: SUVmax measured on (68)Ga-DOTANOC PET/CT is an independent, positive prognostic factor in patients with well-differentiated NET and is superior to SUVmax on (18)F-FDG PET/CT and conventional clinicopathological factors for predicting PFS.

68Ga-DOTATOC PET-CT in the localization of source of ectopic ACTH in patients with ectopic ACTH-dependent Cushing's syndrome.

Localization of the source of adrenocorticotrophic hormone (ACTH) in ectopic ACTH-induced Cushing's syndrome is of paramount importance as definitive management mainly involves surgical resection of tumor. Many of these are occult, not identified by conventional structural imaging. Accurate localization and assessment of their functional status has become feasible with the use positron emission tomography-computerized tomography using (68)Ga-DOTATOC (1,4,7,10-tetraazacy-clododecane-NI,NII,NIII,NIIII-tetraacetic acid(D)-Phe1-thy3-octreotide), aiding in proper planning for their definitive management.

Diagnostic accuracy of (68)Ga-DOTANOC PET/CT imaging in pheochromocytoma.

PURPOSE: The purpose of the present study was to evaluate the diagnostic accuracy of (68)Ga-DOTANOC positron emission tomography (PET)/CT in patients with suspicion of pheochromocytoma. METHODS: Data of 62 patients [age 34.3 ± 16.1 years, 14 with multiple endocrine neoplasia type 2 (MEN2)] with clinical/biochemical suspicion of pheochromocytoma and suspicious adrenal lesion on contrast CT (n = 70), who had undergone (68)Ga-DOTANOC PET/CT, were retrospectively analyzed. PET/CT images were analyzed visually as well as semiquantitatively, with measurement of maximum standardized uptake value (SUVmax), SUVmean, SUVmax/SUVliver, and SUVmean/SUVliver. Results of PET/CT were compared with (131)I-metaiodobenzylguanidine (MIBG) imaging, which was available in 40 patients (45 lesions). Histopathology and/or imaging/clinical/biochemical follow-up (minimum 6 months) was used as reference standard. RESULTS: The sensitivity, specificity, and accuracy of (68)Ga-DOTANOC PET/CT was 90.4, 85, and 88.7%, respectively, on patient-based analysis and 92, 85, and 90%, respectively, on lesion-based analysis. (68)Ga-DOTANOC PET/CT showed 100% accuracy in patients with MEN2 syndrome and malignant pheochromocytoma. On direct comparison, lesion-based accuracy of (68)Ga-DOTANOC PET/CT for pheochromocytoma was significantly higher than (131)I-MIBG imaging (91.1 vs 66.6%, p = 0.035). SUVmax was higher for pheochromocytomas than other adrenal lesions (p = 0.005), MEN2-associated vs sporadic pheochromocytoma (p = 0.012), but no difference was seen between benign vs malignant pheochromocytoma (p = 0.269). CONCLUSION: (68)Ga-DOTANOC PET/CT shows high diagnostic accuracy in patients with suspicion of pheochromocytoma and is superior to (131)I-MIBG imaging for this purpose. Best results of (68)Ga-DOTANOC PET/CT are seen in patients with MEN2-associated and malignant pheochromocytoma.

Novel nucleotide insertions in two unrelated Indian patients with 5α reductase 2 deficiency leading to premature termination of SRD5A2 enzyme.

T is converted to a more potent androgen, DHT by the action of microsomal membrane enzyme 5α reductase 2. Defects in 5α reductase 2 isozyme results in incomplete virilisation of external male genitalia. Mutations in SRD5A2 gene leads to diminished enzyme activity, thus hampering DHT synthesis from T. We describe two unrelated patients from India with 5αRD2 due to novel insertion of nucleotides in the exon 1 of SRD5A2 gene that lead to premature termination of protein. Master S (case 1; III.8) was 3 years old at initial evaluation, had perineoscrotal hypospadias, microphallus and both testes were palpable in the inguinal region. Master P (case 2; III.9) was born as normal full term baby. He had primary complaint of microphallus, penoscrotal hypospadias and gonads in the inguinal region. Diagnosis of 5αRD2 was made, as T/DHT ratio in the two cases was 41 and 131.2 respectively. Sequence analysis of SRD5A2 gene showed an insertion of nucleotides TA in exon 1 (c.188_189). This resulted in premature termination of the protein due to stop codon at amino acid position 7. The protein formed is drastically truncated and inadequate protein synthesized explains the phenotypic characteristics of our patients.

Morning plasma cortisol is low among obese women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common cause for androgen excess in women. It is associated with wide variety of metabolic disorders. The present study assessed morning plasma cortisol in women with PCOS. One hundred and ninety seven cases and 55 controls were enrolled for this study. The mean age of patients and controls were 23 ± 5.6 years and 25 ± 4.3 years. One hundred twelve (56%) women with PCOS had BMI >25. Serum cortisol levels were significantly higher in lean PCOS women compared to controls (13.4 ± 5.1 versus 11.3 ± 4.5, p < 0.01) and over-weight PCOS women group (13.4 ± 5.1 versus 9.3 ± 3.2, p < 0.01). There was a trend for less acne and hirsutism with increase in BMI. Morning plasma cortisol was lower among obese women with PCOS. Morning plasma cortisol correlated negatively with BMI in PCOS women with normal glucose tolerance.

Prenatal treatment of mothers with fetuses at risk for congenital adrenal hyperplasia: How relevant is it to Indian context?

Management of congenital adrenal hyperplasia (CAH) from embryonic stage to adulthood is a critical challenge. We would like to comment on some of the practical difficulties in offering prenatal treatment for CAH-affected fetuses in Indian population. For initiating the prenatal dexamethasone (DEX) treatment, all members of the family need to be informed about the risks and benefits of the treatment to the mother and the fetus as well as about the available invasive diagnostic tests to determine the gender and genotype of the fetus. Prenatal sex disclosure is not routinely practiced in India due to high female feticide rate. The treatment has to be given to both unaffected and affected female fetuses until the determination of prenatal sex. Moreover, most of our populations reside in rural areas where the antenatal care is not adequate. Prenatal DEX treatment in India outruns the risks rather than the benefits, as evident from the literature on the safety of pregnant mothers and fetuses.

Psychosexual outcomes in three siblings with partial androgen insensitivity syndrome: impact of nature versus nurture.

There are few reports of adults with disorders of sexual development (DSD). Here we describe the clinical profile and results of psychological assessment of three siblings with 46, XY DSD caused by partial androgen insensitivity syndrome (PAIS). The elder sibling (aged 22 years) was reared as female, while the middle and youngest siblings (17 and 18 years of age), were reared as males. The gender identity was concordant with the sex of rearing. There was no gender dysphoria. The psychological distress that our patients experienced was due to the limitations placed on them by their medical condition. It did not permit them to experience various facets of being either male or female completely. The younger siblings reared as males had additional problems of gynecomastia and lack of male secondary sexual development.

Internal jugular vein: Peripheral vein adrenocorticotropic hormone ratio in patients with adrenocorticotropic hormone-dependent Cushing's syndrome: Ratio calculated from one adrenocorticotropic hormone sample each from right and left internal jugular vein during corticotrophin releasing hormone stimulation test.

BACKGROUND: DEMONSTRATION OF CENTRAL: Peripheral adrenocorticotropic hormone (ACTH) gradient is important for diagnosis of Cushing's disease. AIM: THE AIM WAS TO ASSESS THE UTILITY OF INTERNAL JUGULAR VEIN (IJV): Peripheral vein ACTH ratio for diagnosis of Cushing's disease. MATERIALS AND METHODS: Patients with ACTH-dependent Cushing's syndrome (CS) patients were the subjects for this study. One blood sample each was collected from right and left IJV following intravenous hCRH at 3 and 5 min, respectively. A simultaneous peripheral vein sample was also collected with each IJV sample for calculation of IJV: Peripheral vein ACTH ratio. IJV sample collection was done under ultrasound guidance. ACTH was assayed using electrochemiluminescence immunoassay (ECLIA). RESULTS: Thirty-two patients participated in this study. The IJV: Peripheral vein ACTH ratio ranged from 1.07 to 6.99 (n = 32). It was more than 1.6 in 23 patients. Cushing's disease could be confirmed in 20 of the 23 cases with IJV: Peripheral vein ratio more than 1.6. Four patients with Cushing's disease and 2 patients with ectopic ACTH syndrome had IJV: Peripheral vein ACTH ratio less than 1.6. Six cases with unknown ACTH source were excluded for calculation of sensitivity and specificity of the test. CONCLUSION: IJV: Peripheral vein ACTH ratio calculated from a single sample from each IJV obtained after hCRH had 83% sensitivity and 100% specificity for diagnosis of CD.

Diagnosis and management of classical congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is among the most common genetic disorders. Deficiency of adrenal steroid 21-hydroxylase deficiency due to mutations in the CYP21A2 gene accounts for about 95% cases of CAH. This disorder manifests with androgen excess with or without salt wasting. It also is a potentially life threatening disorder; neonatal screening with 17-hydroxyprogesterone measurement can diagnose the condition in asymptomatic children. Carefully monitored therapy with glucocorticoid and mineralocorticoid supplementation will ensure optimal growth and development for children with CAH. Genital surgery may be required for girls with CAH. Continued care is required for individuals with CAH as adults to prevent long-term adverse consequences of the disease, including infertility, metabolic syndrome and osteoporosis.

Internal jugular vein adrenocorticotropic hormone estimation for diagnosis of adrenocorticotropic hormone-dependent Cushing's syndrome: Ultrasound-guided direct jugular vein sample collection.

AIM OF STUDY: To assess the utility of internal jugular vein (IJV) / peripheral adrenocorticotropic hormone (ACTH) gradient in determining the etiology of ACTH- dependent Cushing's syndrome. MATERIALS AND METHODS: Patients with ACTH-dependent Cushing's syndrome, (except children less than 12 years), had IJV blood collection under ultrasound guidance using a linear 7 MHZ probe. Blood was collected with a 21 G needle at the level of mandible with the patient in supine position. Six ml of blood was collected sequentially from right and left internal jugular veins for ACTH and prolactin estimation. Peripheral blood for ACTH and prolactin was taken from a previously placed IV cannula in the antecubital vein. RESULTS: Thirty patients (20 F, 10 M, age 14 to 50 yrs) were enrolled for this study. Source of ACTH excess was pituitary in 22, ectopic ACTH in 4, and unknown in 4 cases. Using an IJV: Peripheral ACTH ratio of ≥ 1.6, 15 out of 22 Cushing's disease patients were correctly identified. However, 1 out of 4 ectopic Cushing also had IJV: Peripheral ratio ≥ 1.6. Overall, it had sensitivity of 68% with specificity of 75% while MRI pituitary and HDDST had sensitivity of 86% and 59%, respectively, with specificity of 100% each. CONCLUSION: IJV: Peripheral ACTH gradient was observed in 68% of patients with Cushing's disease. Simultaneous IJV and peripheral sample collection with CRH stimulation may improve sensitivity and specificity of this test.

Hypokalemic paralysis as a presenting manifestation of primary Sjögren's syndrome: A report of two cases.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by a progressive lymphocytic infiltration of the exocrine glands with varying degrees of systemic involvement. Overt or latent renal tubular acidosis (RTA), caused by tubulointerstitial nephropathy, is a common extraglandular manifestation of pSS. Hypokalemic paralysis is a well known, albeit rare complication of severe distal RTA from any cause. Cases of pSS manifesting for the first time as hypokalemic paralysis caused by distal RTA have been rarely reported. We herein present our experience of two cases, who presented to us for evaluation of hypokalemic paralysis and on work up found evidence of distal RTA, which on further work up found to be secondary to pSS. A high index of suspicion for pSS should be kept in all patients with hypokalemic paralysis.

Development of Graves' disease after long-standing hypothyroidism on treatment, with acute toxicity to thionamides and lithium.

Thyroid hyperfunction in a patient with long-standing hypothyroidism is uncommon. Here, we describe and discuss the unusual scenario of development of severe skin rash to carbimazole, with subsequent acute toxicity to lithium in clinically indicated doses, in a patient who manifested hyperthyroidism after being on treatment for hypothyroidism for 7 years.

Pubertal development among girls with classical congenital adrenal hyperplasia initiated on treatment at different ages.

INTRODUCTION: Children with congenital adrenal hyperplasia (CAH) provide us an opportunity to study the clinical effects of androgen excess in humans. We studied the sequence of pubertal development in girls with congenital adrenal hyperplasia initiated on treatment at different ages, to assess the effects of androgen exposure on the Hypothalamic-Pituitary-Ovarian (HPO) axis. MATERIALS AND METHODS: Girls more than 18 years of age, with CAH, on follow-up at this hospital were the subjects for this study. Details of history, physical findings, laboratory evaluation, and medication were noted from their case records and verified from the patients and their / parents, in addition to assessment of their present health status. RESULT: We studied 24 patients of classical CAH (SW-2, SV-22, average age - 24.5 ± 6.6 years). All had varying degrees of genital ambiguity (Prader stage 3 (n = 13), Prader stage 2 (n = 10), Prader stage 1 (n = 1). Among them were13 girls, who were started on steroids after eight years of age. Girls who received treatment from infancy and early childhood had normal pubertal development (mean age at menarche 11.4 ± 1.7 years). Hirsutism was not a problem among them. Untreated children had progressive clitoral enlargement throughout childhood, developed pubic hair at around three to six years of age, and facial hair between nine and eleven years. Plasma testosterone ranged from 3 to 6 ng / ml prior to treatment. Six of the 13 untreated CAH girls had subtle breast development starting at ages 11 - 16 years and three had spontaneous infrequent vaginal bleeding starting at ages 11 - 17. Steroid supplementation initiated pubertal changes in older girls in two-to-six months' time. CONCLUSION: There was a delay in HPO axis maturation (as evidenced by delayed pubertal development) in the absence of treatment in girls with CAH. This could be corrected with steroid supplementation.

Molecular genetic analysis of CYP21A2 gene in patients with congenital adrenal hyperplasia.

CONTEXT: Congenital adrenal hyperplasia (CAH) is one of the inborn errors of metabolic disorder inherited in an autosomal recessive manner caused by the defects in the steroid 21 hydroxylase CYP21A2 gene. We analyzed the genotype of 62 patients with classic CAH. AIMS: To find out the underlying mutations of CYP21A2 gene. SETTINGS AND DESIGN: Cohort of CAH patients. MATERIALS AND METHODS: Sixty-two patients with CAH were recruited from the endocrine clinic at AIIMS. Electrochemiluminiscence method was used for estimating the levels of cortisol. Radioimmunoassay kit-based method was used for estimating the 17 OHP levels. Polymerase chain reaction amplification was done using specific primers to amply the CYP21A2 gene. STATISTICAL ANALYSIS USED: Statistical analysis was done by using Epi Info Version 3.5.1.2008. RESULTS: Out of 62 patients, 50 were simple virilizers (SV) and 12 were salt wasters (SW). Fifty-six were females and six were males. Five 46, XX children were reared as males. Age at presentation varied from 8 months to 38 years. Molecular genetic analysis revealed that the highest number of patients harboured (In 2) IVS2-13 A/C > G (48%), followed by p.P30L (46%), p.Q318X (35%), (D 8 bp) deletion 8 bp (26%), p.I172N (26%), and p. R356W (20%) mutations. CONCLUSION: This is among the few studies to analyze the mutational spectrum of CYP21A2 gene in a large CAH cohort from India. Molecular diagnosis of CYP21A2 gene should be considered as part of the CAH evaluation to assess the risk of the patients/parents/siblings and to offer genetic counseling.