A girl with two syndromes: Turner syndrome and Costello syndrome. A case history

Turner syndrome (TS, OMIM#300706) is a well-defined chromosomal disorder characterized by short stature, gonadal dysgenesis (lack of spontaneous pubertal development), and somatic stigmata [Nielsen and Wohlert, 1991] associated with complete or partial absence of the second X chromosome. Patients with a small distal short arm deletion (Xp-) including the SHOX gene frequently have short stature and other TS associated skeletal anomalies, but most are at low risk of ovarian failure and generally should not be diagnosed with TS if band Xp22.3 is not deleted [Ross et al., 2001]. Costello syndrome (CS; OMIM 218040) is a rare autosomal dominant complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to develop neoplasia [reviewed by Gripp and Lin, 2009]. It is caused by activating germline mutations in the HRAS gene, encoding an important protein in the RAS-MAPK signaling pathway. We report on a Caucasian girl with a deletion of a short arm of chromosome X and Costello syndrome. She was the first child born to non-consanguineous parents at 35 weeks’ gestation by cesarean because of fetal distress on heart rate monitor. No polyhydramnios was reported. Her birth weight was 2200 g (10th centile), length was 46 cm (50th centile), and head circumference was 32 cm (50th centile). Soon after birth, she was noted to have somedysmorphic features, although the only information recorded was that of low-set ears and hypotonia. Chromosome analysis performed using peripheral blood leukocytes showed a karyotype of 46,X,del(X)(p21.2). Turner syndromewas diagnosed [Ross et al., 2001; Bondy, 2007]. Parental chromosomes were normal. Echocardiogram performed in the neonatal period was normal and electrocardiography showed first degree AV block. The neonatal coursewas complicatedbyhypoglycemia, intracranial hemorrhage, and severe anemia that required two blood transfusions. She received parenteral nutrition until the age of 8 days, and due to poor breastfeeding she required additional nutrition with nasogastric tube for several days. After discharge she was bottle fed at home and systematically gained weight. At the age of 1 year she had macrocephaly, a short, webbed neck, hypertelorism, bilateral epicathal folds,widely spacednipples, deepplantar andpalmar creases, and hyperconvex nails, but no further genetic studies were performed. Her psychomotor development was delayed. She sat at 1 year, started to walk at 2 years, and spoke her first words at 1.5 years of age. At the age of 7 years growth hormone (GH) replacement therapy was started and continued until age 13 years. Her growth improved from the 5th to over 95th centile on Turner girls growth charts (Fig. 1). At 9 years of age, due to features of spontaneous puberty (Tanner breast stage II, pubic hair stage I) and results of hormonal studies, gonadotropin-releasing hormone agonist therapy (Triptorelin) was started and continued for 2 years. The echocardiogramat8 years of agewasnormal, but at 9 years of age there was concentric left ventricular (LV) hypertrophy with a peak LV pressure gradient of 58mm of mercury. Therapy with a non-selective beta blocker (propranolol)was started and continued with a selective B1 blocker (metoprolol). Although this was an unusual phenotype for Turner syndrome, she was not referred to the genetic department until she was 13 years old. She exhibited striking dysmorphic features including relative macrocephaly, coarse face with thick lips (Fig. 2A,B), hypertelorism with downslanting palpebral fissures, macrostomia, macroglossia, increased skin pigmentation, wrinkled, loose skin of hands (Fig. 3A,B) and feet, hyperconvex and uplifted nails, perioral and nasal papillomata (Fig. 2), joint laxity, sparse eyebrows, curly and sparse hair. Her