Digital Hypoplasia Research Articles

Fryns syndrome: A clinical conundrum

Fryns syndrome is an uncommon autosomal recessive disorder with ocular signs and multisystem involvement with features like diaphragmatic defect, pulmonary hypoplasia, characteristic facial appearance, distal digital hypoplasia, etc., Associated ocular features reported till date are cloudy cornea, microphthalmos, hypertelorism, and retinal dysplasia. The pathogenesis of the syndrome is not well understood although mutations in PIGN gene in clinically diagnosed cases have been reported. Based on a French population study, the prevalence reported was 7 in 100,000 live births, but this prevalence was established before the advent of many genetic testing methodologies. Currently, there are no additional prevalence reports available. We report a 7-month-old female child who presented to us with recurrent acute on chronic dacryocystitis along with microcornea and iridofundal coloboma. Child underwent detailed systemic examination and was clinically diagnosed as Fryns syndrome.

Hypothesis: Central digit hypoplasia.

Limb deficiencies are a common birth defect. A malformations surveillance program among many newborns, stillborn fetuses, and malformed fetuses in elective terminations can identify a sufficient number of infants with the same set of abnormalities to characterize a specific limb deficiency phenotype. The active malformations surveillance program was carried out among 289,365 births at Brigham and Women's Hospital in Boston over a 41-year period (1972-2012). The research assistants identified the affected infants and fetuses from reading the findings recorded in each newborn's medical record by the examining pediatricians and consultants and by the pathologists in autopsies. One hundred ninety-four newborn infants and fetuses were found to have a limb deficiency either as an isolated abnormality or as one of multiple malformations. We identified three phenotypes of limb deficiency. We present here the seventeen infants and fetuses with "central digit hypoplasia," a term we suggest for this phenotype: hypoplasia of the thumb and fifth finger with nubbins of soft tissue in place of fingers 2, 3, and 4 at the level of the metacarpal-phalangeal joint. Central digit hypoplasia is to be distinguished primarily from the terminal transverse limb defect that ends at the wrist. In symbrachydactyly, the middle and distal phalanges of the fingers and toes are hypoplastic. In addition, central digit hypoplasia should be distinguished from the amniotic band syndrome, the most common and incorrect diagnosis suggested by the pediatricians and the consultants in this survey. The affected infant and her/his parents benefit from more accurate and specific counseling.

Physical features of newborns exposed during pregnancy to anticonvulsant medication and developmental monitoring

Antiepileptic drug (AED) use during pregnancy can affect the physical features, intelligence, and behavior in the exposed infants and children. Identifying these AED-related effects early makes intervention in childhood possible. To examine the accuracy of the identification of AED effects on the physical features of newborn infants, the written findings in routine physical examinations in medical records can be evaluated. Documentation of AED exposure and the physical findings recorded was obtained from the hospital medical records of 207 infants at a large birthing hospital. Comparison was made of the findings in these infants by private pediatricians and two study pediatricians who were unaware of infant exposure status. The comparisons of the findings were analyzed using the Kappa statistic. The level of agreement in the assessment of the presence of facial features characteristic of midface hypoplasia by private pediatricians and the study pediatricians was poor (Kappa=0.04; 95 CI-0.07 to 0.01); for microcephaly was fair (Kappa=0.39; CI-0.14 to 0.93); and for growth restriction was fair (Kappa-0.22; CI-0.18 to 0.63). Findings recorded by hospital pediatricians in medical records during routine medical care showed that most (74%) of the pediatricians were aware of the infant's exposure to AED during pregnancy. Pediatricians did not do well in identifying the physical signs of midface or digit hypoplasia or microcephaly or growth restriction. Better early identification of the physical effects from AED exposure would make it possible for infants to benefit from developmental monitoring.

Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3\u2014a subgroup of K+ channelopathies

Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann–Laband and Temple–Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.

Antenatal sonographic diagnosis of fryns syndrome: A case report

Fryns et al described a syndrome in the year 1979.1 Fryns syndrome is characterized by diaphragmatic defects, facial dysmorphism including coarse face, hypertelorism, broad and flat nasal bridge, with thick nasal tip, long philtrum, tented upper lip, wide mouth, micrognathia, low set and poorly formed ears and distal digital hypoplasia, pulmonary hypoplasia and others.2 We report a case of fryns syndrome in twenty- nine years old, Chinese, primigravida diagnosed during antenatal ultrasound scan at 26 weeks of gestation. The diagnosis has been confirmed by clinical finding, ultrasound, X-ray chest, CT brain, and ECHO at the postnatal period. Keywords: Fryns syndrome, Diaphragmatic hernia, Microphthalmia, Lung hypoplasia polyhydramnios.

Fryns Syndrome Associated with Recessive Mutations in PIGN in two Separate Families.

Fryns syndrome is an autosomal recessive condition characterized by congenital diaphragmatic hernia (CDH), dysmorphic facial features, distal digital hypoplasia, and other associated malformations, and is the most common syndromic form of CDH. No gene has been associated with this condition. Whole-exome sequence data from two siblings and three unrelated individuals with Fryns syndrome were filtered for rare, good quality, coding mutations fitting a recessive inheritance model. Compound heterozygous mutations in PIGN were identified in the siblings, with appropriate parental segregation: a novel STOP mutation (c.1966C>T: p.Glu656X) and a rare (minor allele frequency <0.001) donor splice site mutation (c.1674+1G>C) causing skipping of exon 18 and utilization of a cryptic acceptor site in exon 19. A further novel homozygous STOP mutation in PIGN (c.694A>T: p.Lys232X) was detected in one unrelated case. All three variants affected highly conserved bases. The two remaining cases were negative for PIGN mutations. Mutations in PIGN have been reported in cases with multiple congenital anomalies, including one case with syndromic CDH. Fryns syndrome can be caused by recessive mutations in PIGN. Whether PIGN affects other syndromic and non-syndromic forms of CDH warrants investigation.

Unusual association of choanal atresia, digital hypoplasia, simian crease, cortical atrophy and hemiparesis with congenital cytomegalovirus infection

Cytomegalovirus (CMV) is one of the most common congenital viral infections in humans. It can follow both primary and recurrent maternal infections and is an important cause of morbidity and mortality in newborns. The effects of congenital CMV infection vary widely from asymptomatic illness to a congenital syndrome with microcephaly, jaundice, hepatosplenomegaly and petechiae. Infants who are asymptomatic at birth may still present with sensorineural hearing loss, mental retardation and neuromuscular defects at a later age. We report a full term, small-for-gestational age neonate with congenital CMV infection who presented with unusual clinical features, including choanal atresia, digital hypoplasia, simian crease, blueberry muffin rash, cortical atrophy and hemiparesis.

Congenital constriction ring of limbs in subjects with history of maternal substance use.

Congenital Constriction Ring (CCR) is a rare malformation which manifests itself in the form of ring-like constrictive bands. Due to its heterogeneous nature, its etiology remains unclear. Here, we present a series of seven independent individuals afflicted with CCR, which primarily involved the digits. The phenotypic manifestations included terminal phalangeal reduction, anonychia, digit hypoplasia, and acrosyndactyly. Mesoaxial digits in hands and preaxial digits in feet were most frequently affected. Camptodactyly and clubfoot were witnessed in four and one subject, respectively. Curiously, mothers of six of these subjects revealed that they consumed copious amounts of Multani mitti(Fuller's clay) and/or Naswar(nonsmoke-tobacco), during their respective pregnancies. Maternal substance use during pregnancy is not an unusual practice, however, its relationship with CCR as pregnancy outcome remains unexplored. Case-control studies are warranted to elucidate the relationship between the exposure to these substances and the etiology of CCR and/or other limb defects in the offspring.

Yunis-Varón Syndrome Is Caused by Mutations in FIG4, Encoding a Phosphoinositide Phosphatase

Yunis-Varón syndrome (YVS) is an autosomal-recessive disorder with cleidocranial dysplasia, digital anomalies, and severe neurological involvement. Enlarged vacuoles are found in neurons, muscle, and cartilage. By whole-exome sequencing, we identified frameshift and missense mutations of FIG4 in affected individuals from three unrelated families. FIG4 encodes a phosphoinositide phosphatase required for regulation of PI(3,5)P(2) levels, and thus endosomal trafficking and autophagy. In a functional assay, both missense substitutions failed to correct the vacuolar phenotype of Fig4-null mouse fibroblasts. Homozygous Fig4-null mice exhibit features of YVS, including neurodegeneration and enlarged vacuoles in neurons. We demonstrate that Fig4-null mice also have small skeletons with reduced trabecular bone volume and cortical thickness and that cultured osteoblasts accumulate large vacuoles. Our findings demonstrate that homozygosity or compound heterozygosity for null mutations of FIG4 is responsible for YVS, the most severe known human phenotype caused by defective phosphoinositide metabolism. In contrast, in Charcot-Marie-Tooth disease type 4J (also caused by FIG4 mutations), one of the FIG4 alleles is hypomorphic and disease is limited to the peripheral nervous system. This genotype-phenotype correlation demonstrates that absence of FIG4 activity leads to central nervous system dysfunction and extensive skeletal anomalies. Our results describe a role for PI(3,5)P(2) signaling in skeletal development and maintenance.

Congenital diaphragmatic hernia with hypoplastic lungs, heart, and additional anomalies: A case of ? Fryns syndrome

Congenital diaphragmatic hernia (CDH) is a common congenital anomaly that frequently occurs in conjunction with other major anomalies, including chromosomal abnormalities. Fryns syndrome (FS) is a lethal syndrome that most frequently features CDH as a cardinal feature in addition to pulmonary hypoplasia, coarse facies, distal digital hypoplasia, and organ malformations. The exact genetic defect has not yet been identified, although it is regarded to follow an autosomal recessive pattern of inheritance. We describe the autopsy findings of a medically terminated 20 weeks fetus with left-sided CDH, hypoplastic left heart, lungs, horse-shoe kidney and other anomalies, confirming to the phenotypic diagnostic guidelines of FS.

Long-term Donor Site Morbidity After Free Nonvascularized Toe Phalangeal Transfer

Free nonvascularized toe phalangeal transfer is an established surgical option for the reconstruction of hypoplastic digits. This study assessed long-term morbidity in the feet using this technique. We reviewed 40 children treated between 1991 and 2007 by free nonvascularized toe phalangeal transfer. The diagnosis was digital hypoplasia resulting from symbrachydactyly in 33 cases, constriction ring syndrome in 3 cases, thumb hypoplasia in 3 cases, and perinatal subclavian venous thrombosis in 1 case. The patients were followed up after surgery for a mean of 10 years (range, 3-19 y). The Oxford Ankle Foot Questionnaire was administered to patients and families to assess patient symptoms and patient and parental satisfaction. We assessed toe length ratio, the presence of visible deformity, and distal hypoplasia of the donor toes clinically and radiographically. Emotional problems related to foot appearance were common. We also found functional problems with footwear in some patients. All patients had floppy unstable toes with visible deformity. Increasing foot deformity was seen with growth, which led to deterioration in foot aesthetics, particularly where multiple donor toes had been harvested. We identified distal and middle phalangeal and metatarsal hypoplasia in the donor toes. Donor site morbidity for free toe phalangeal transfer is greater than previously documented. This should be considered during surgical decision making for reconstruction of hypoplastic digits. Preoperative counseling should include discussion regarding possible consequences of phalangeal harvest on donor toes and options for donor site reconstruction. Long-term follow-up of the donor site is essential to accurately assess results. Therapeutic III.

The Role of the Pediatrician in Preventing Congenital Malformations

The Role of the Pediatrician in Preventing Congenital Malformations

An interesting clinical association of short neck with an unusual laryngeal anomaly

An elongated high-rising epiglottis can represent a normal variation of the larynx in a majority of pediatric patients. However, there are virtually no reports available for visible or high-rising epiglottis on routine oral examination in adult patients without upper respiratory tract inflammation. We report an unusual case with prominently visible epiglottis on oral examination. We diagnosed him with a rare congenital disorder based on associated physical examination and imaging evidence of short neck, low hair line, Sprengel's anomaly, left digital hypoplasia, restricted neck movements, cervical vertebra fusion, and mirror movements (synkinesia).

Petty syndrome and Fontaine–Farriaux syndrome: Delineation of a single syndrome

In 1990, Petty et al. described two patients representing a novel syndrome with "congenital progeriod" features and neither had classical progeria nor Wiedemann-Rautenstrauch syndrome, though many findings were overlapping. One of the cases had previously been described by Dr. Wiedemann in 1948. The key features of Petty syndrome include pre and postnatal growth restriction, decreased subcutaneous fat with loose skin, enlarged fontanelle with underdeveloped calvarium, coronal synostosis, unruly hair pattern with non-uniform distribution, prominent eyebrows, umbilical hernia, distal digital hypoplasia, and normal or near normal development. Significant overlap to other syndromes, particularly the Fontaine-Farriaux syndrome, is apparent. In 2004, Ardinger postulated that Petty syndrome, like classical progeria, might be secondary to a defect in the lamin A/C (LMNA) gene. The purpose of this paper is to describe two new unrelated cases of this unique syndrome that further delineate the phenotype, compare to phenotypically similar syndromes, and postulate that Petty syndrome could represent a new laminopathy. In addition, evidence suggesting that the Petty syndrome and Fontaine-Farriaux syndromes are variable expressions of the same condition is discussed.

CHILD syndrome: the NSDHL gene and its role in CHILD syndrome, a rare hereditary disorder

CHILD syndrome, a rare hereditary disorder of keratinization (MIM 308050, 300275), is the acronym proposed by Happle to name a rare entity, characterized by congenital hemidysplasia, icthyosiform nevus and limb defects, ranging from digital hypoplasia to icthyosiform nevus and ipsilateral limb defects, ranging from digital hypoplasia to complete amelia. A 9-month-old female infant presented with skin and limb defects involving the right side of her body. Clinical and laboratory evaluation was performed, including DNA sequence analysis of the NSDHL gene. Our patient presented with some of the typical clinical characteristics of CHILD syndrome, i.e. two large erythematous plaques with sharp borders, covered with yellow, wax-like scaling, on the right axilla and on the right groin, dysplastic right hand and alopecia of the right occipital area. The diagnosis was confirmed by DNA screening analysis, that detected a missense mutation c.314C-->T;p-A105V, in the coding region of the NSDHL gene (exon4) of our patient. This is the first report of CHILD syndrome ever reported in Greece. We suggest that the diagnosis of the syndrome is important for patient information and genetic counselling.

Familial multiple ventricular extrasystoles, short stature, craniofacial abnormalities and digital hypoplasia: a further case of Stoll syndrome?

We report two brothers, their mother and a maternal cousin who had a distinctive facial phenotype, mild brachydactyly and prominence of the interphalangeal joints. One brother and the mother also had multiple ventricular extrasystoles. Six other relatives in four generations were probably affected on the basis of history and family photographs. We also report a further individual from a different family with a similar facial phenotype, Pierre-Robin sequence, tapering fingers and multiple ventricular extrasystoles. These families have some similarities to those reported by Stoll et al. in a single family, showing dominant inheritance. Our patients would seem to have the same or a related condition.

EEC syndrome, Arg227Gln TP63 mutation and micturition difficulties: Is there a genotype–phenotype correlation?

We report on two unrelated families with EEC syndrome (ectrodactyly, ectodermal dysplasia, cleft lip/palate), each with an Arg227Gln TP63 gene mutation, where the phenotype overlapped extensively with the allelic disorder, limb-mammary syndrome (LMS). Features common to both families were an ectodermal dysplasia principally affecting tooth, breast and nipple development, dacryostenosis and severe micturition difficulties. Additional findings included post-axial digital hypoplasia, cleft uvula, anal stenosis, hypoplasia of the perineal body and biopsy-proven interstitial cystitis. No individual had cleft lip. Split hand-split foot malformation (SHFM) occurred in one child-born after the molecular diagnosis was established. Unlike previous reports, the urinary symptoms were refractory to treatment with oral Fibrase and persisted into adulthood. Of the six cases/families now reported with EEC syndrome and Arg227Gln TP63 mutation, four have manifested this distinct urological abnormality, indicative of a genotype-phenotype correlation.

Cardiovascular malformations in Fryns syndrome: Is there a pathogenic role for neural crest cells?

We performed a comprehensive literature and case report review to characterize the cardiovascular malformations (CVMs) associated with Fryns syndrome (OMIM #229850), a multiple congenital anomaly/mental retardation syndrome consisting of diaphragmatic defects, significant pulmonary hypoplasia, distinctive facial appearance, distal digital hypoplasia, and numerous other external and internal anomalies. A total of 112 patients meeting diagnostic guidelines for Fryns syndrome were identified, of whom 82 met narrowly defined criteria (Group I) and 30 met broader diagnostic criteria (Group II). Twelve patients reported as having Fryns syndrome with atypical features (Group III) were also analyzed. A CVM was reported in 51% (42 of 82) of Group I patients, most commonly an atrial or ventricular septal defect (VSD) (23 of 42, 55%). Conotruncal and aortic arch CVMs were common (11 of 42, 26%), but not significantly so compared to the general population of infants to age 1 year [Ferencz et al., 1997]. Recognizing that minor septal defects associated with congenital diaphragmatic hernia (CDH) may occur in response to altered hemodynamics (instead of being a bonafide CVM), we excluded four patients reported as having hemodynamically insignificant VSDs. Following these exclusions, conotruncal CVMs were found more commonly than in the general population (11 of 38, 29%, P < or = 0.025). In Group II, 9 of 30 (30%) had a CVM with no predominant type among the small number of cases reviewed. Among the atypical Fryns syndrome patients in Group III, half (6 of 12, 50%) had a CVM; most (4 of 6, 67%) were conotruncal, in particular, type B interrupted aortic arch (3 of 4). Patients with Fryns syndrome have a high rate of CVMs, warranting thorough cardiac evaluation including echocardiogram (fetal and/or postnatal) in all patients, similar to the evaluation for other patients with diaphragmatic hernia. The possible association between conotruncal CVMs and Fryns syndrome may provide additional support for an etiologic role of genes related to neural crest cell development in the pathogenesis of Fryns syndrome and hence, congenital diaphragmatic hernia.

The correlation of deficits in IQ with midface and digit hypoplasia in children exposed in utero to anticonvulsant drugs

Children exposed during pregnancy to the anticonvulsant drugs phenytoin, phenobarbital, and carbamazepine as monotherapy and polytherapy have an increased frequency of midface and digit hypoplasia. Some children also have cognitive dysfunction. The hypothesis tested is that the anticonvulsant drug-exposed child with midface and digit hypoplasia is more likely to have cognitive dysfunction. Children exposed to anticonvulsant drugs (n = 80) were recruited for a follow-up evaluation, which included testing cognitive function and a physical examination for head size, height, and the presence of midface and digit hypoplasia. Microcephaly, midface and digit hypoplasia, and major malformations were correlated with full scale (FSI), performance (PIQ) and verbal (VIQ) intelligence. The presence of the 3 anticonvulsant-exposed children with microcephaly had a deficit of 23.7 IQ points in FSI in comparison with the other children with a normal head size. Either midface or digit hypoplasia, after excluding the persons with microcephaly and with the Bonferroni correction, correlated significantly with deficits in VIQ (-12.7), PIQ (-10) and FSI (-12.8) IQ points ( P = .0061). There was no decrease in IQ in association with major malformations. The presence of midface and digit hypoplasia in a child exposed to anticonvulsant drugs in pregnancy is an indication for a systematic developmental evaluation.

Nonvascularized toe phalangeal bone grafts for congenital anomalies of the hand

Digital hypoplasia or aplasia can result from both longitudinal and transverse deficiencies. The indications for and technique of nonvascularized toe phalangeal bone grafts to stabilize and lengthen the soft-tissue sleeve of the digit is described.