Congenital heart defects associated with aneuploidy syndromes: New insights into familiar associations

The frequent occurrence of congenital heart defects (CHDs) in chromosome abnormality syndromes is well‐known, and among aneuploidy syndromes, distinctive patterns have been delineated. We update the type and frequency of CHDs in the aneuploidy syndromes involving trisomy 13, 18, 21, and 22, and in several sex chromosome abnormalities (Turner syndrome, trisomy X, Klinefelter syndrome, 47,XYY, and 48,XXYY). We also discuss the impact of noninvasive prenatal screening (mainly, cell‐free DNA analysis), critical CHD screening, and the growth of parental advocacy on their surgical management and natural history. We encourage clinicians to view the cardiac diagnosis as a “phenotype” which supplements the external dysmorphology examination. When detected prenatally, severe CHDs may influence decision‐making, and postnatally, they are often the major determinants of survival. This review should be useful to geneticists, cardiologists, neonatologists, perinatal specialists, other pediatric specialists, and general pediatricians. As patients survive (and thrive) into adulthood, internists and related adult specialists will also need to be informed about their natural history and management.     

The trichorhinophalangeal syndrome with repeated dislocation of the patella

The trichorhinophalangeal syndrome associated with laxity of the skin and joints has been mistaken for Ehlers-Danlos syndrome (Jones 1988). We report a case of the trichorhinophalangeal syndrome which we mistook for the Larsen syndrome. Literature and published photographs of the Larsen syndrome are reviewed to highlight the similarities between these two entities. These observations may be of value in the genetic mapping of the Larsen syndrome, which perhaps is a contiguous gene syndrome.     

Variability in the Smith-Lemli-Opitz syndrome: Overlap with the meckel syndrome

The syndromes of Smith-Lemli-Opitz (RSH) and of Meckel are usually clinically distinct but have many overlapping manifestations. In rare instances it may be difficult to distinguish them, especially if an autopsy is not done. Attention to detail is essential for accurate delineation. Two other syndromes, the C and Hydrolethalus, should be considered in the differential diagnosis.     

Hajdu-Cheney syndrome with severe dural ectasia

Hajdu-Cheney syndrome (HCS) is an autosomal dominant condition comprising osteolysis of the terminal phalanges, characteristic craniofacial abnormalities, dental anomalies, and proportionate short stature. The clinical and radiological findings develop and progress with age. Here, we report on a HCS patient with severe scoliosis and exceptionally massive dural ectasia. Congenital scoliosis and dural ectasia have not been reported previously in HCS.     

Antley-Bixler syndrome and esophageal atresia in a patient with trisomy 21

The Antley-Bixler syndrome (ABS) is characterized by craniofacial, skeletal and urogenital anomalies. While most patients with ABS die of severe respiratory complications in their first months, long-term survivors have been reported. We report an infant girl, born to a consanguineous couple, with craniofacial and skeletal anomalies, consistent with ABS, in addition to atresia of the esophagus and trisomy 21.     

XXY male with X-linked dominant chondrodysplasia punctata (Happle syndrome)

Happle syndrome is an X-linked dominant disorder with presumed lethality in hemizy-gous males; familial occurrence is rare. We describe a family with Happle syndrome affecting individuals in 3 generations. A man in this family is the first known male patient with Happle syndrome. He is severely affected; this may be due to his 47, XXY kary-Otype. © 1995 Wiley-Liss, Inc.     

Insulin resistance in patients with polycystic ovary syndrome is associated with elevated plasma homocysteine

BACKGROUND: Elevated levels of plasma homocysteine have recently been implicated as a significant risk factor for cardiovascular disease, pre-eclampsia, and recurrent pregnancy loss, and have been found to be associated with insulin resistance in a number of clinical situations. We examined the relationship between plasma homocysteine and insulin resistance in patients with polycystic ovary syndrome (PCOS). METHODS: A total of 155 infertile patients with PCOS as defined by clinical, biochemical and ultrasound criteria were screened for insulin resistance utilizing single-sample fasting insulin and glucose measurement, calculated by glucose:insulin ratio or homeostasis model assessment (HOMA) index. Total plasma homocysteine was measured by fluorescence polarization immunoassay. One hundred normo-ovulatory women with normal ovaries being treated for other infertility diagnoses served as a control group. RESULTS: Insulin resistance was found in the majority of PCOS patients: -53.5% (83/155), 60.6% (94/155) and 65.8% (102/155), when defined by fasting insulin, glucose:insulin ratio, or logHOMA respectively. Mean plasma homocysteine in the PCOS group was significantly higher than in the normal ovary group (11.5 +/- 7.4 versus 7.4 +/- 2.1 micromol/l, P < 0.001). Insulin-resistant PCOS patients had significantly higher plasma homocysteine (12.4 +/- 8.4 micromol/l) than non-insulin-resistant PCOS patients (9.6 +/- 4.4 micromol/l) regardless of body mass index (P = 0.003 by groups, P = 0.005 by correlation of single samples). Thirty-four per cent (53/155) of the PCO patients had homocysteine values >95th percentile of the controls (11.0 micromol/l, P < 0.0001). Statistically significant correlations were found between all insulin resistance indices and homocysteine levels. Multiple logistic regression defined insulin resistance as the major factor examined that influenced homocysteine levels. CONCLUSIONS: Insulin resistance and hyperinsulinaemia in patients with PCOS is associated with elevated plasma homocysteine, regardless of body weight. This finding may have important implications in the short term regarding reproductive performance, and in the long term regarding cardiovascular complications associated with insulin-resistant PCOS.     

PHACE syndrome: Infantile hemangiomas associated with multiple congenital anomalies: Clues to the cause

Infantile hemangiomas (IH) are the most common vascular tumor of infancy with an estimated 80,000 annual diagnoses in the United States. The genetic mechanisms underlying IH and the related multi-organ birth defect syndromes, PHACE (an acronym for P osterior fossa brain malformations, segmental facial H emangiomas, A rterial anomalies, C ardiac defects, E ye anomalies, and sternal clefting or supraumbilical raphe) and LUMBAR (an acronym for L ower body hemangiomas, U rogenital anomalies, M yelopathy, B one deformities, A norectal malformations/ A rterial anomalies, R enal anomalies) remain unsolved. With advances in next generation sequencing (NGS), genomic alterations have been identified in a wide range of vascular anomaly syndromes. We hypothesize that PHACE is a genetic disorder, caused by somatic mutations, likely in cancer genetic pathways. Identification of the genetic etiology will lead to improved diagnosis in PHACE syndrome and development of targeted therapies for IH and related congenital anomalies.     

儿童肾病综合征并发血栓8例分析

目的探讨儿童肾病综合征（NS）并发血栓的种类和特点。方法回顾性分析北京大学第一医院儿科1996年7月至2011年5月NS并发血栓患儿的临床资料,对血栓发生年龄、部位、症状、血清学指标和短期预后进行总结。结果 8例NS并发血栓患儿进入分析,其中男7例,女1例,发生血栓的平均年龄为10.6岁。患儿以头痛、呕吐、抽搐、腹痛、血便、肉眼血尿、咯血或胸闷等症状就诊。静脉血栓6例（75%）,见于门静脉、肠系膜上静脉、肺栓塞、肾静脉、下腔静脉、颅内静脉,其中肺栓塞3例,肾静脉血栓2例,颅内静脉血栓2例;动脉血栓2例,左胫前动脉和颈内动脉血栓各1例。3例颅内血栓通过头颅MR I和MRV或MRA确诊,其余部位血栓分别通过血管超声、肺灌注显像和CT检查确诊。7例患儿血清白蛋白〈20 g.L-1,8例患儿血浆纤维蛋白原〉4 g.L-1,7例患儿血D-二聚体增高。8例患儿确诊后均予以肝素、尿激酶、华法林或双嘧达莫等抗凝及溶栓治疗,2例患儿经内科治疗无效分别行截肢和肠切除术。近期随访血栓或相关症状消失或改善。结论 NS患儿肺栓塞发生情况可能并不少于肾静脉血栓。对于10岁左右男性,伴显著低白蛋白血症、高纤维蛋白原血症和血D-二聚体增高者可能更需警惕血栓,应尽早行影像学检查。     

Two sisters with Escobar syndrome

We report on 2 sisters with an autosomal-recessive multiple pterygium syndrome, type Escobar, consisting of multiple pterygia with severe contractures, short stature, and minor facial and external genital anomalies. The striking finding was severe muscular atrophy. We speculate that a neu-romuscular disorder is the underlying pathogenesis of Escobar syndrome. © 1995 Wiley-Liss, Inc.     

Long-term evaluation of a child with the branchio-oculo-facial syndrome

We report on the 12-year development of a child with branchio-oculo-facial syndrome who was initially referred at age 5 months. Of note is his normal intelligence, regular class placement, hypernasal speech, and continued growth along the third centile. The importance of serial observations of patients with rare genetic disorders is emphasized. © 1992 Wiley-Liss, Inc.     

Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence

Noonan syndrome (NS) and related disorders are caused by mutations in various genes encoding molecules involved in the RAS–MAPK signalling cascade. There are strong genotype–phenotype correlations. BRAF is the major gene for cardio-facio-cutaneous syndrome (CFCS), and usually patients with a BRAF mutation have significant cognitive impairment. We report on a patient with LEOPARD syndrome and normal intelligence who was found to carry a novel sequence change in BRAF. The mutation p.L245F was demonstrated to be de novo with no evidence of somatic mosaicism. This observation illustrates that the phenotypic spectrum caused by BRAF mutations is broader than previously assumed and that mental retardation is not necessarily associated. We speculate that the impact of p.L245F on BRAF protein function differs either qualitatively or quantitatively from those mutations associated with CFCS.     

Gorlin-like phenotype in a patient with a PTCH2 variant of uncertain significance

Gorlin syndrome, also known as Nevoid Basal-Cell Carcinoma Syndrome (NBCCS), is an autosomal dominant tumor predisposition syndrome that presents early in life with characteristic congenital malformations and tumors. This syndrome most commonly results from germline mutations of the PTCH1 tumor suppressor gene, which shows high penetrance and great intra and interfamilial phenotypic variability, as well as the SUFU tumor suppressor gene. Recently, the PTCH2 gene has also been implicated as a cause of Gorlin syndrome. Notably, these patients displayed milder phenotypes of Gorlin syndrome when considered against PTCH1 and SUFU-related disease.We report a patient with a novel PTCH2 mutation inherited from his father. The proband displays several minor diagnostic features of Gorlin syndrome, supporting the pathogenic role of this gene. Features in the proband include macrocephaly, a wide face, prominent forehead, hypertelorism/telecanthus, large eyes, cleft lip and palate, thin vertical palmar creases, penoscrotal inversion, and a hyperpigmented spot on his penis. His father displays macrocephaly, several nevi on his back and shoulders, and a single palmar pit on his left hand, raising suspicion for Gorlin syndrome. Whole exome sequence (trio) found that the proband and father are heterozygous for NM_003738.4:c.3347C>T;p.(Pro1116Leu) in exon 21 of PTCH2, found also in his mildly affected brother. This semi-conservative amino acid substitution has been reported in the literature, but its significance is unclear. Notably, the proband, brother, and father do not meet clinical criteria for Gorlin syndrome. However, the clinical findings described in this family support the association between PTCH2 mutations and Gorlin-like phenotypes.     

Analysis of prevalence and degree of macrocephaly in patients with germline PTEN mutations and of brain weight in Pten knock-in murine model

PTEN Hamartoma Tumour Syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and other conditions resulting from germline mutation of the PTEN tumour suppressor gene. Although macrocephaly, presumably due to megencephaly, is found in both CS and BRRS, the prevalence and degree have not been formally assessed in PHTS. We evaluated head size in a prospective nested series of 181 patients found to have pathogenic germline PTEN mutations. Clinical data including occipital-frontal circumference (OFC) measurement were requested for all participants. Macrocephaly was present in 94% of 161 evaluable PHTS individuals. In patients ≤ 18 years, mean OFC was +4.89 standard deviations (SD) above the population mean with no difference between genders (P = 0.7). Among patients >18 years, average OFC was 60.0 cm in females and 62.8 cm in males (P < 0.0001). To systematically determine whether macrocephaly was due to megencephaly, we examined Pten(M3M4) missense mutant mice generated and maintained on mixed backgrounds. Mice were killed at various ages, brains were dissected out and weighed. Average brain weight for Pten(M3M4) homozygous mice (N = 15) was 1.02 g compared with 0.57 g for heterozygous mice (N = 29) and 0.49 g for wild-type littermates (N = 24) (P < 0.0001). Macrocephaly, secondary to megencephaly, is an important component of PHTS and more prevalent than previously appreciated. Patients with PHTS have increased risks for breast and thyroid cancers, and early diagnosis is key to initiating timely screening to reduce patient morbidity and mortality. Clinicians should consider germline PTEN testing at an early point in the diagnostic work-up for patients with extreme macrocephaly.     

OCRL mutation analysis in Italian patients with Lowe syndrome

The oculocerebrorenal syndrome of Lowe (OCRL, also called OCRL1) is a rare X-linked disorder characterized by major abnormalities of eyes, nervous system, and kidneys. The gene responsible for OCRL was identified by positional cloning and encodes an inositol polyphosphate-5-phosphatase. We performed the molecular analysis in 9 Italian patients and 26 relatives and we detected the mutations in all the examined patients. Eight mutations out of nine had never been described and consisted of truncating mutations (frameshift, nonsense, splice site and genomic deletion), and missense mutations. The mutations were distributed in the second half of the gene as previously described in other populations. In three cases the mutations were absent in the mothers confirming the occurrence of novel mutations in this disorder. Our results on the Italian population are similar to the data previously obtained in other populations.     

Tricho-Rhino-Phalangeal syndrome type II (Langer-Giedion) with persistent cloaca and prune belly sequence in a girl with 8q interstitial deletion

A patient with the diagnosis of Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome type II) and interstitial 8q deletion was also noted to have persistent cloaca and prune belly sequence. This is the first report of this association. If it postulated that these latter embryonic defects may be due to the chromosome abnormality, supporting the definition of contiguous gene syndrome. © 1992 Wiley-Liss, Inc.     

Pain in individuals with RASopathies: Prevalence and clinical characterization in a sample of 80 affected patients

Pain in individuals with RASopathies is a neglected topic in literature. In this article, we assessed prevalence and profile of pain in a sample of 80 individuals affected by RASopathies. The study sample included individuals with Noonan syndrome (N = 42), Costello syndrome (N = 17), and cardio‐facio‐cutaneous syndrome (N = 21). A set of standardized questionnaires and scales were administered (VAS/numeric scale, r‐FLACC, Wang‐Baker scale, NPSI, BPI, NCCPC‐R) to detect and characterize acute and chronic pain and to study the influence of pain on quality of life (PEDs‐QL, SF‐36) and sleeping patterns (SDSC); revision of past medical history and multisystemic evaluation was provided. Available clinical data were correlated to the presence of pain. High prevalence of acute (44%) and chronic (61%) pain was documented in the examined sample. Due to age and intellectual disability, acute pain was localized in 18/35 individuals and chronic pain in 33/49. Muscle‐skeletal and abdominal pain was more frequently reported. The intensity of acute and chronic pain interfered with daily activities in 1/3 of the sample. Pain negatively impacted on QoL and sleeping patterns. This work documents that pain is highly prevalent in RASopathies. Future studies including subjective and objective measures of pain are required to discriminate a somatosensory abnormality from an abnormal elaboration of painful stimuli at a central level.     

Holt-Oram syndrome associated with the hypoplastic left heart syndrome

We present the first case of Holt-Oram syndrome associated with the lethal congenital heart defect of hypoplastic left heart syndrome. The possible pathophysiological link is explored and the need for careful genetic and cardiologic evaluation in these patients is reiterated.