Smith-Lemli-Optiz syndrome: importance of ophthalmology referral and follow-up.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by mutations in the 7-dehydrocholesterol reductase (DHCR7) gene, located on chromosomal region 11q13. This results in reduced cholesterol and increased 7-dehydrocholesterol (7DHC) levels. Accumulation of 7DHC in patients with SLOS can affect multiple organs and display a broad phenotypic expression. Ophthalmic abnormalities related to SLOS are variable but the most common is blepharoptosis. Over 50% of these patients present with self-injurious behavior, such as head banging, which can result in ocular complications and blindness. We report the first case of peripheral avascularity of the retina in a patient with SLOS. Physicians should be aware of the potential ocular complications associated with SLOS and confounding factors, such as prematurity, given that referral is usually delayed due to the lack of awareness of these potentially blinding associations. This case highlights the importance of early referral and continuous ophthalmologic follow-up in preventing further deterioration of visual development and complications that can lead to blindness.

Smith-Lemli-Opitz syndrome - Fetal phenotypes with special reference to the syndrome-specific internal malformation pattern.

BACKGROUND: Autosomal-recessive SLOS is caused by mutations in the DHCR7 gene. It is defined as a highly variable complex of microcephaly with intellectual disability, characteristic facies, hypospadias, and polysyndactyly. Syndrome diagnosis is often missed at prenatal ultrasound and fetal autopsy METHODS: We performed autopsies and DHCR7 gene analyses in eight fetuses suspected of having SLOS and measured cholesterol values in long-term formalin-fixed tissues of an additional museum exhibit RESULTS: Five of the nine fetuses presented classical features of SLOS, including four cases with atrial/atrioventricular septal defects and renal anomalies, and one with additional bilateral renal agenesis and a Dandy-Walker cyst. These cases allowed for diagnosis at autopsy and subsequent SLOS diagnosis in two siblings. Two fetuses were mildly affected and two fetuses showed additional holoprosencephaly. These four cases and the exhibit had escaped diagnosis at autopsy. The case with bilateral renal agenesis presented a novel combination of a null allele and a putative C-terminus missense mutation in the DHCR7 gene CONCLUSIONS: In view of the discrepancy between the prevalence of SLOS among newborns and the carrier frequency of a heterozygous DHCR7 gene mutation, the syndrome-specific internal malformation pattern may be helpful not to miss SLOS diagnosis in fetuses at prenatal ultrasound and fetal autopsy.

Prenatal diagnosis of holoprosencephaly associated with Smith-Lemli-Opitz syndrome (SLOS) in a 46,XX fetus.

OBJECTIVE: To show the importance of measuring cholesterol precursor levels in amniotic fluid in all pregnancies with ultrasound features (such as holoprosencephaly) suggestive of Smith-Lemli-Opitz syndrome (SLOS), after exclusion of chromosomal anomalies. CASE REPORT: A 28-year-old woman, gravida 1 para 0, performed chorionic villus sampling for fetal karyotyping at 13 weeks of gestation due to positive combined first trimester screening in a fetus with increased nuchal translucency and suspected holoprosencephaly. The result was normal - 46,XX. The diagnosis of alobar holoprosencephaly was confirmed at 15 weeks of gestation, and cardiac and limb defects were also identified. Thus, a syndromic cause was considered, specifically a chromosomal microdeletion syndrome or a monogenic entity such as SLOS. The latter was confirmed by measuring 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) in amniotic fluid. Molecular analysis of DHCR7 gene identified a homozygous mutation in intron 8, c.964-1G>C, providing molecular confirmation for this diagnosis. CONCLUSION: The differential diagnosis of holoprosencephaly is broad. Identification of the cause of holoprosencephaly aids in establishing the prognosis and is essential to ascertain the mode of inheritance for adequate genetic counseling.

Síndrome de Smith-Lemli-Opitz e hipotiroidismo: el primer caso venezolano / Smith-Lemli-Opitz syndrome and hypothyroidism: the first Venezuelan case

El síndrome de Smith-Lemli-Opitz (SSLO) es un desorden metabólico autosómico recesivo debido a la síntesis anormal de colesterol y fue descrito por primera vez por Smith, Lemli y Opitz en 1964. Muchos casos de SSLO han sido descritos desde entonces, siendo reconocido como un síndrome malformativo relativamente común. Los individuos afectados tienen dismorfismo, microcefalia, múltiples malformaciones congénitas, retraso mental, agresividad e hiperactividad. La severidad de los defectos físicos se correlaciona con la severidad de la deficiencia de colesterol, la cual es causada por la baja actividad de la 7-dehidrocolesterol reductasa, enzima responsable de la conversión de 7-dehidrocolesterol a colesterol. La ocurrencia de hipotiroidismo en asociación con SSLO es muy inusual. Este constituye el primer caso venezolano en el que se asocian ambas patologías.

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive metabolic disorder due to an abnormal cholesterol synthesis. It was first described by Smith, Lemli and Opitz in 1964. Many cases of SLOS have been described since then, leading to the recognition as a relatively common malformation syndrome. Affected individuals have dysmorphism, microcephaly, multiple congenital malformations, mental retardation, aggressiveness and hyperactivity. The severity of physical defects correlates with the severity of the cholesterol deficiency, which is caused by an abnormally low activity of 7-dehydrocholesterol reductase, the enzyme responsible for conversion of 7-dehydrocholesterol to cholesterol. The occurrence of hypothyroidism in association with SLOS is very unusual. We describe the first Venezuelan case in which both anomalies are associated.

Live birth after PGD with confirmation by a comprehensive approach (karyomapping) for simultaneous detection of monogenic and chromosomal disorders.

Preimplantation genetic diagnosis (PGD) for monogenic disorders has the drawback of time and cost associated with tailoring a specific test for each couple, disorder, or both. The inability of any single assay to detect the monogenic disorder in question and simultaneously the chromosomal complement of the embryo also limits its application as separate tests may need to be carried out on the amplified material. The first clinical use of a novel approach ('karyomapping') was designed to circumvent this problem. In this example, karyomapping was used to confirm the results of an existing PGD case detecting both chromosomal abnormalities and a monogenic disorder (Smith-Lemli-Opitz [SLO] syndrome) simultaneously. The family underwent IVF, ICSI and PGD, and both polar body and cleavage stage biopsy were carried out. Following whole genome amplification, array comparative genomic hybridisation of the polar bodies and minisequencing and STR analysis of single blastomeres were used to diagnose maternal aneuploidies and SLO status, respectively. This was confirmed, by karyomapping. Unlike standard PGD, karyomapping required no a-priori test development. A singleton pregnancy and live birth, unaffected with SLO syndrome and with no chromosome abnormality, ensued. Karyomapping is potentially capable of detecting a wide spectrum of monogenic and chromosome disorders and, in this context, can be considered a comprehensive approach to PGD.

Obstetric, perinatal, and fetal outcomes in pregnancies with false-positive integrated screening results.

OBJECTIVE: To assess the risk of adverse obstetric, perinatal, and fetal outcomes for pregnant women participating in prenatal sequential integrated screening through the California Prenatal Screening Program who had a false-positive screening result. METHODS: Women who underwent first- and second-trimester prenatal integrated screening plus nuchal translucency measurement with outcome information available were included. Fetuses and neonates with chromosomal or neural tube defects were excluded. We compared the risk of adverse outcomes for all women with a positive screening result compared with a 10% random sample of women with a negative screening result. Logistic binomial regression was used to compare adverse outcomes in screen-positive compared with screen-negative women. RESULTS: We identified 9,051 screen-positive and 30,928 screen-negative pregnancies with outcome information available. Compared with screen-negative pregnancies, screen-positive women were more likely to be diagnosed with preeclampsia, placenta previa, or abruption (7.6% screen-positive, 3.8% screen-negative; relative risk 1.7, 95% confidence interval [CI] 1.6-1.8) or experience fetal loss before 20 weeks of gestation (1.9% screen-positive, 0.2% screen-negative; relative risk 3.5, 95% CI 3.2-3.8). Women with positive results for more than one screened condition were at substantially greater risk of fetal and neonatal mortality (relative risks 33.6-156.7, 95% CIs 21.8-194.4). CONCLUSION: Among pregnancies without chromosomal or neural tube defects, prenatal sequential integrated screening provides information regarding risk across a variety of adverse pregnancy outcomes.

Autism spectrum disorders and inborn errors of metabolism: an update.

BACKGROUND: Autism spectrum disorder is characterized by social communicative deficits with restricted interests occurring in about 1% of the population. Although its exact cause is not known, several factors have been implicated in its etiology, including inborn errors of metabolism. Although relatively uncommon, these disorders frequently occur in countries with high rates of consanguinity and are often associated with behavioral problems, such as hyperactivity and aggression. The aim of this review is to examine the association of autism with these conditions. METHOD: A computer-assisted search was performed to identify the most common inborn errors of metabolism associated with autism. RESULTS: The following disorders were identified: phenylketonuria, glucose-6-phosphatase deficiency, propionic acidemia, adenosine deaminase deficiency, Smith-Lemli-Opitz syndrome and mitochondrial disorders, and the recently described branched chain ketoacid dehydrogenase kinase deficiency. CONCLUSION: The risk of autistic features is increased in children with inborn errors of metabolism, especially in the presence of cognitive and behavioral deficits. We propose that affected children should be screened for autism.

Brain magnetic resonance imaging findings in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a neurodevelopmental disorder caused by inborn errors of cholesterol metabolism resulting from mutations in 7-dehydrocholesterol reductase (DHCR7). There are only a few studies describing the brain imaging findings in SLOS. This study examines the prevalence of magnetic resonance imaging (MRI) abnormalities in the largest cohort of patients with SLOS to date. Fifty-five individuals with SLOS (27 M, 28 F) between age 0.17 years and 25.4 years (mean = 6.2, SD = 5.8) received a total of 173 brain MRI scans (mean = 3.1 per subject) on a 1.5T GE scanner between September 1998 and December 2003, or on a 3T Philips scanner between October 2010 and September 2012; all exams were performed at the Clinical Center of the National Institutes of Health. We performed a retrospective review of these imaging studies for both major and minor brain anomalies. Aberrant MRI findings were observed in 53 of 55 (96%) SLOS patients, with abnormalities of the septum pellucidum the most frequent (42/55, 76%) finding. Abnormalities of the corpus callosum were found in 38 of 55 (69%) patients. Other findings included cerebral atrophy, cerebellar atrophy, colpocephaly, white matter lesions, arachnoid cysts, Dandy-Walker variant, and type I Chiari malformation. Significant correlations were observed when comparing MRI findings with sterol levels and somatic malformations. Individuals with SLOS commonly have anomalies involving the midline and para-midline structures of the brain. Further studies are required to examine the relationship between structural brain abnormalities and neurodevelopmental disability in SLOS.

Probing lipid-protein adduction with alkynyl surrogates: application to Smith-Lemli-Opitz syndrome.

Lipid modifications aid in regulating (and misregulating) protein function and localization. However, efficient methods to screen for a lipid's ability to modify proteins are not readily available. We present a strategy to identify protein-reactive lipids and apply it to a neurodevelopmental disorder, Smith-Lemli-Opitz syndrome (SLOS). Alkynyl surrogates were synthesized for polyunsaturated fatty acids, phospholipids, cholesterol, 7-dehydrocholesterol (7-DHC), and a 7-DHC-derived oxysterol. To probe for protein-reactive lipids, we used click chemistry to biotinylate the alkynyl tag and detected the lipid-adducted proteins with streptavidin Western blotting. In Neuro2a cells, the trend in amount of protein adduction followed known rates of lipid peroxidation (7-DHC >> arachidonic acid > linoleic acid >> cholesterol), with alkynyl-7-DHC producing the most adduction among alkynyl lipids. 7-DHC reductase-deficient cells, which cannot properly metabolize 7-DHC, exhibited significantly more alkynyl-7-DHC-protein adduction than control cells. Model studies demonstrated that a 7-DHC peroxidation product covalently modifies proteins. We hypothesize that 7-DHC generates electrophiles that can modify the proteome, contributing to SLOS's complex pathology. These probes and methods would allow for analysis of lipid-modified proteomes in SLOS and other disorders exhibiting 7-DHC accumulation. More broadly, the alkynyl lipid library would facilitate exploration of lipid peroxidation's role in specific biological processes in numerous diseases.

Cholesterol metabolism deficiency.

Genetic defects in enzymes responsible for cholesterol biosynthesis have emerged as important causes of congenital dysmorphology and retardation syndromes. Cholesterol is an important constituent of the cell membrane of most eukaryotic cells, in myelin formation in the brain, spinal cord, and peripheral nervous system, and acts as the precursor for steroid hormones and bile acids. Finally, cholesterol has important interactions with proteins, which control embryonic development. To date, eight distinct inherited disorders have been linked to different defects in cholesterol biosynthesis. Two result from an enzyme defect in the pre-squalene segment of the pathway: the classical form of mevalonic aciduria and the hyperimmunoglobulinemia D syndrome, also known as Dutch-type periodic fever. Six defects in the post-squalene segment of the pathway include: Smith-Lemli-Opitz syndrome, two X-linked dominant inherited and male-lethal disorders, Conradi-Hünermann-Happle syndrome and congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD), and at least three extremely rare autosomal recessive disorders, Greenberg skeletal dysplasia, lathosterolosis, and desmosterolosis. All these inborn errors known to date have been linked to deficiency of specific enzymes on the basis of elevated levels of specific sterol intermediates in tissues of affected patients followed by demonstrating disease-causing mutations in the encoding genes. These cholesterol deficiency multiple malformation-retardation syndromes have clinical overlap. Besides psychomotor retardation, developmental delay, structural brain malformations, multiple congenital anomalies, microcephaly, and cataract, impaired cholesterol biosynthesis is associated with autism and other behavioral disorders.

Prenatal presentation and diagnostic evaluation of suspected Smith-Lemli-Opitz (RSH) syndrome.

Smith-Lemli-Opitz (SLOS), or RSH syndrome, is an autosomal recessive deficiency of 7-dehydrocholesterol reductase (DHCR7) resulting in an accumulation of 7- and 8-dehydrocholesterol (7- and 8-DHC) in tissues and body fluids. At birth patients have variable malformations of CNS, heart, kidney, genitalia, and limbs, which may be life-limiting. In later course, psychomotor and mental retardation and behavior abnormalities become evident. Prenatally SLOS can be suspected on the basis of malformations and intrauterine growth retardation (IUGR) in prenatal ultrasonography and reduced maternal free estriol in serum. The diagnosis is confirmed by sterol analysis in a chorionic villus biopsy or amniotic fluid (AF). In this study, we evaluated the predictive value of the above mentioned criteria in combination with family history by quantification of sterols in AF in pregnancies with either a family history, ultrasonographical abnormalities typical for SLOS, or reduced maternal serum unconjugated estriol (MSuE3). The relative frequency of SLOS in fetuses with an affected sibling was 0.23, as to be expected for an autosomal recessive disease. The probability for SLOS was <0.6% when neither an affected sib nor more than one typical SLOS malformation was present. For safety reasons and for cost-effectiveness we recommend careful evaluation of history, MSuE3, and clinical presentation before determining sterols in AF.

Sterol profiles in plasma and erythrocyte membranes in patients with Smith-Lemli-Opitz syndrome: a six-year experience.

BACKGROUND: This study reports our experience over the last six years in the diagnosis of Smith-Lemli-Opitz syndrome and other inborn errors of cholesterol biosynthesis. METHODS: Gas chromatography/mass spectrometry was used to obtain sterol profiles in plasma and erythrocyte membranes of suspected patients. RESULTS: Plasma sterol reference values calculated in unaffected subjects (n=276) were in agreement with those previously reported. Among patients investigated from 2005 to 2010, we report 16 patients affected by Smith-Lemli-Opitz syndrome, three of whom represent new cases and 13 of whom were follow-up patients. In this period we also identified a new case of chondrodysplasia punctata 2 X-linked. The estimated incidence obtained for Smith-Lemli-Opitz syndrome was 1:93 suspected patients (1.08%). We also studied the effect of storage on the dehydrocholesterols/cholesterol ratio in plasma and erythrocyte membranes of patients affected by Smith-Lemli-Opitz syndrome stored at -20°C for up to 22 and 20 months, respectively. A significant negative linear correlation between storage time and the dehydrocholesterols/cholesterol ratio was identified in both plasma and erythrocyte membranes. The decrease in the dehydrocholesterols/cholesterol ratio in erythrocyte membranes was at least two-fold higher than in plasma. CONCLUSIONS: The results of this study may be helpful for diagnosis and interpretation of data in patients with findings suggestive of a cholesterol biosynthesis defect.

Detection rate of quadruple-marker screening determined by clinical follow-up and registry data in the statewide California program, July 2007 to February 2009.

OBJECTIVE: To evaluate the efficiency of California's quadruple-marker screening program and construct receiver-operating characteristic (ROC) curves. METHODS: This study included the screening records of 552 941 women during July 2007 to February 2009. The screen-positive women received clinical follow-up services at state-approved centers. We used the California Chromosome Defect Registry which includes clinical, laboratory, and demographic data from the prenatal diagnostic centers, cytogenetic laboratories, hospitals, and prenatal care providers. Risk calculations, screen-positive rates (SPRs), detection rates (DRs) for chromosomal abnormalities, and 95% confidence intervals (95% CIs) were determined. ROC curves comparing the quadruple-marker to triple-marker screening were constructed. RESULTS: The DR and SPR for trisomy 21 (N = 827) during the quadruple-marker time period were 75.7% (95% CI 72.8-78.6%) and 3.75% (95% CI 3.70-3.80%) compared with 77.4% (95% CI 75.0-79.7%) and 5.4% during the triple-marker phase. The DRs were 78.2% (95% CI 75.0-81.4%) with ultrasound dating and 66.9% (95% CI 59.7-74.0%) for last-menstrual-period-dated pregnancies. For trisomy 18, triploidy, and trisomy 13, the DRs were 84.3, 95.7, and 43.5%, respectively. CONCLUSIONS: The DR for trisomy 21 in California's statewide quadruple-marker screening is very similar to the Program's previously reported DR using triple-marker screening. However, this was achieved at a lower SPR, demonstrating improved screening performance.

Rehabilitación oral de un paciente pediátrico con síndrome de Smith-Lemli-Opitz bajo anestesia general ambulatoria / Oral rehabilitation of a pediatric patient with smith-lemli-opitz syndrome under outpatient general anesthesia

El síndrome de Smith-Lemli-Opitz es una rara enfermedad hereditaria de transmisión autosómica recesiva. Se caracteriza por presenta hipocolesterolemia como consecuenciade una mutación del gen 7-deshidrocolesterol reductasa (7DHCR), lo que produce retrasomental, retardo en el crecimiento, microcefalia, micrognatismo y otras anomalías neurológicas sistémicas y físicas. Se presenta el caso de un paciente de tres años y nueve mesesafectado por este síndrome, quien acudió a la clínica de odontología pediátrica de la Facultad de Odontología de la Universidad Autónoma de Baja California, Tijuana, donde se inició historia médica y dental. Debido a su corta edad, la presencia de múltiples lesiones cariosas, conducta incontrolable, retraso mental y compromiso sistémico, se decidió realizar larehabilitación oral del paciente bajo anestesia general, la cual se describe detalladamente...

Smith-Lemli-Opitz syndrome is a rare autosomal recessive hereditary disease. It is caused by a mutation in the 7-dehydrocholesterol reductase (DHCR7) gene producing hypocholesterolemia,and consequence mental retardation, delayed growth, microcephaly, micrognathia and other systemic neurological and physical features. A case of a three-year-ninemonth-old patient affected by this syndrome who attended the Pediatric Dental Clinic of the Universidad Autónoma de Baja California Dental School at Tijuana is presented. Afterdoing medical and dental records and because of his young age, multiple dental cavities, uncontrollable behavior, mental retardation and medical status, oral rehabilitation under general anesthesia was performed. The anesthesia procedure is detailed...

Idiopathic persistent pulmonary hypertension in an infant with Smith-Lemli-Opitz syndrome.

Persistent pulmonary hypertension (PPHN) of the newborn remains a challenging condition to diagnose and treat. It has been reported in infants with Smith-Lemli-Opitz syndrome (SLOS), a rare defect in cholesterol synthesis. Typically, there is evidence of pulmonary hypoplasia. We report the first case of PPHN in the absence of pulmonary hypoplasia or other parenchymal diseases in an infant with SLOS. Perturbations in cholesterol metabolism interrupt key signaling pathways that participate in the normal maintenance of pulmonary vascular tone. We found that caveolae-dependent signaling may be involved in this process since our patient had altered expression of caveolin-1.

Diagnostic determination system for high-risk screening for inborn errors of bile acid metabolism based on an analysis of urinary bile acids using gas chromatography-mass spectrometry: results for 10 years in Japan.

BACKGROUND: Some patients with cholestasis of unknown cause may have inborn errors of bile acid metabolism (IEBAM) thus causing abnormalities of bile acid biosynthesis. Although seven types of bile acid synthetic defects have thus far been reported for this disorder, no detailed information on its incidence and so on in Japan is yet available. In order to elucidate the current status of IEBAM in Japan, in July 1996 a diagnostic determination system was established for high-risk screening for IEBAM. METHODS: Urinary bile acids were analyzed on gas chromatography-mass spectrometry (GC-MS) and quantitative analysis was done using selected ion monitoring (SIM). RESULTS AND CONCLUSIONS: In a total of 576 samples analyzed over the 10 year period prior to June 2005, 159 patients were found with cholestasis of unknown etiology. Of these patients, 10 (6.3%) were found to have IEBAM by this system, while 91 (61.1%) had cholestasis without a definitive diagnosis. This diagnostic determination system with GC-MS of urinary bile acids is therefore considered useful for detecting IEBAM.

Molecular screening of Smith-Lemli-Opitz syndrome in pregnant women from the Czech Republic.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive metabolic disorder. SLOS is caused by the mutations in the gene for 3beta-hydroxysterol Delta(7) reductase (DHCR7; EC 1.3.1.21), which maps to chromosome 11q12-13. DHCR7 catalyses the final step in cholesterol biosynthesis-the reduction of 7-dehydrocholesterol to cholesterol. Clinical severity ranges from mild dysmorphism to severe congenital malformation and intrauterine lethality. Pregnant women are offered a biochemical screening test for Down syndrome in the second trimester, where the suspicion for SLOS could be registered, when the unconjugated estriol (uE3) level appears low. A group of 456 fetuses with a high risk for SLOS were examined by DNA analysis. We confirmed SLOS in 5 fetuses and 11 fetuses were carriers. One novel mutation (p.G30A) was detected. The most frequently found mutations, c.964-1G > C and p.W151X, are also the most severe ones. At least one of these mutations was detected in each fetus with SLOS. This suggests that the biochemical screening of pregnant women probably uncovers mainly more severely affected fetuses. We confirmed SLOS also in two patients whose prenatal screening was negative. Both of them had nonsense mutation on one allele. It stands to reason that some modifying factors may play a role in the reduction of the uE3 level in the mother's serum.

Major fetal abnormalities associated with positive screening tests for Smith-Lemli-Opitz syndrome (SLOS).

OBJECTIVE: Determine the relationship between positive screening interpretations for Smith-Lemli-Opitz syndrome (SLOS) and other fetal abnormalities, to aid counseling and diagnostic activities. METHODS: An SLOS screening algorithm was incorporated into California's second-trimester screening program for Down syndrome and open neural tube defects (ONTDs). Between 2002 and 2004, 777 088 pregnant women were given an SLOS risk interpretation, using alpha-fetoprotein (AFP), unconjugated estriol (uE3), and human chorionic gonadotrophin (hCG) measurements. Outcomes were obtained in 98.8% of screen-positive pregnancies. RESULTS: SLOS screen positives, alone or in combination with screen positives for other fetal disorders (Down syndrome, trisomy 18, ONTD), were associated with a high risk for fetal pathology. Type and frequency of chromosomal or anatomic abnormalities (or fetal death) varied according to screen-positive combination. Among 2018 screen-positive pregnancies, 644 fetal deaths were identified. Among the 1374 viable pregnancies, 519 were screen positive for SLOS alone; two SLOS cases and 51 other serious abnormalities were identified (14 aneuploidies; 37 anatomic). The remaining 855 were also screen positive for at least one other disorder; two SLOS cases and 327 other abnormalities were identified (180 aneuploidies; 157 anatomic). CONCLUSION: For screening programs implementing the SLOS algorithm, the present data may be useful for counseling and to guide diagnostic studies.