The SALL4 gene encodes a transcription factor that is essential for early embryonic cellular differentiation of the epiblast and primitive endoderm. It is required for the development of neural tissue, kidney, heart, and limbs. Pathogenic SALL4 variants cause Duane-radial ray syndrome (Okihiro syndrome), acro-renal-ocular syndrome, and Holt-Oram syndrome. We report a family with vertical transmission of a SALL4 pathogenic variant leading to radial hypoplasia and kidney dystopia in several generations with additional growth hormone deficiency (GHD) in the proband. Our male proband was born at the 39th week of gestation. He was born small for gestational age (SGA; birth weight 2,550 g, -2.2 SDS; length 47 cm, -2.0 SDS). He had bilateral asymmetrical radial ray malformation (consisting of radial hypoplasia, ulnar flexure, and bilateral aplasia of the thumb) and pelvic kidney dystopia, but no cardiac malformations, clubfoot, ocular coloboma, or Duane anomaly. He was examined for progressive short stature at the age of 3.9 years, where his IGF-1 was 68 μg/L (-1.0 SD), and growth hormone (GH) after stimulation 6.2 μg/L. Other pituitary hormones were normal. A brain CT revealed normal morphology of the cerebral midline and the pituitary. He had a dental anomaly - a central mandibular ectopic canine. MRI could not be done due to the presence of metal after multiple corrective plastic surgeries of his hands. His mother's and father's heights are 152.3 cm (-2.4 SD) and 177.8 cm (-0.4 SD), respectively. His father has a milder malformation of the forearm. The affected paternal grandfather (height 164 cm; -2.3 SD) has a radial ray defect with missing opposition of the thumb. The family reports a similar phenotype of radial dysplasia in the paternal grandfather's mother. The proband started GH therapy at age 6.5 years when his height was 109 cm (-2.8 SDS) and he experienced catch-up growth as expected in GHD. Puberty started spontaneously at the age of 12.5 years. At age 13, his height was 158.7 cm (-0.2 SDS). Whole-exome sequencing revealed a nonsense variant in the SALL4 gene c.1717C>T (p.Arg573Ter) in the proband, his father, and paternal grandfather. This is the first observation of a patient with a congenital upper limb defect due to a pathogenic SALL4 variant who has isolated GHD with no apparent cerebral or facial midline anomaly and has been successfully treated with growth hormone. SALL4-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and SALL4-related Holt-Oram syndrome (HOS) – three phenotypes previously thought to be distinct entities. DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly). AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. Rarely, pathogenic variants in SALL4 may cause clinically typical HOS (i.e., radial ray malformations and cardiac malformations without additional features). The diagnosis of a SALL4-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in SALL4 identified by molecular genetic testing. Treatment of manifestations: Surgery as needed for strabismus from Duane anomaly, malformations of the forearms, and congenital heart defects; management of renal anomalies per nephrologist and/or urologist; antiarrhythmic medications or pacemaker for those with conduction defects or heart block; cardiologist can assist in determining the need for anticoagulants and antibiotic prophylaxis for bacterial endocarditis; hearing aids as needed; consideration of growth hormone therapy for children with growth deficiency; treatment of pituitary hypoplasia per endocrinologist. Surveillance: Ophthalmologic exam with frequency as recommended by ophthalmologist; monitor renal function in those with renal anomalies, even if renal function is normal initially; periodic renal ultrasound evaluation if renal position anomalies could cause obstruction; periodic echocardiographic surveillance may be recommended for individuals with certain congenital heart defects; in those at risk for conduction defects, EKG at least annually with consideration of annual Holter monitor in those with known conduction defects; at least annual blood counts in those with a history of thrombocytopenia and leukocytosis; audiologic evaluation as needed; assessment of growth and for signs and symptoms of pituitary hypoplasia at each visit. Agents/circumstances to avoid: Drugs affecting the kidney if renal function is impaired, or the inner ear if hearing is impaired; certain medications may be contraindicated in those with arrhythmias. SALL4-related disorders are inherited in an autosomal dominant manner. The proportion of cases caused by a de novo pathogenic variant is approximately 40%-50%. Each child of an individual with a SALL4-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant has been identified in an affected family member.

Thalidomide remains notorious as a result of the damage it caused to children born to mothers who used it to treat morning sickness between 1957 and 1961. The re-emergence of the drug to treat a range of conditions including erythema nodosum leprosum (a complication of leprosy) has led to a new generation of thalidomide damaged children being born in Brazil. Although thalidomide affects most of the developing tissues and organs of the body, the damage to the limbs is striking. Indeed phocomelia, the severe reduction or loss of the proximal long bones with retention of the distal hand/foot plate remains the stereotypical image of thalidomide. This review focuses on the type and range of damage thalidomide caused to the limbs, reviews current understanding of the mechanisms underlying thalidomide-induced limb malformations and outlines some of the challenges remaining in elucidating its teratogenicity.

Papillorenal syndrome (PRS), an autosomal dominant inherited condition, is clinically featured by renal hypoplasia and optic nerve dysplasia. Based on current knowledge of genotype-phenotype correlations in PRS, mutations in the Paired box 2 (PAX2) gene have been recognized as a critical pathogenesis of typical renal and optic disease manifestations. However, little information is currently available on the skeletal abnormalities of PRS and the potential contribution of PAX2 mutations. Here, we present a case of a 10-year-old female PRS patient with the typical features of chronic renal failure and severe myopia, but was unexpectedly discovered camptodactyly of her left middle finger which affects the proximal interphalangeal joint. Pathologically, the camptodactyly was further indicated by radiology as a skeletal deformity, demonstrating a decline of bone mineral density and disappearance of joint space. Molecular diagnostics revealed a heterozygous mutation, 220_225dup, in the exon 3 of her PAX2 gene, which is de novo considering the lack of this mutation in her non-consanguineous parents. This mutation leads to duplication of glutamic acid at position 74 and tyrosine at position 75 in PAX2 protein, which may influence the DNA-binding function. Besides, the absence of Spalt like transcription factor 4 (SALL4) mutation excluded the diagnosis of acro-renal-ocular syndrome (AROS), of which clinical characteristics are similar to our patient's. This case unravels a previously unrecognized phenotype of camptodactyly due to a significant skeletal deformity of PRS with a heterogeneous PAX2 mutation of hexanucleotide duplication. This report challenges against the current belief of genotype-phenotype correlations in PRS.

To investigate the genetic etiology of anophthalmia and microphthalmia, we used exome sequencing in a Caucasian female with unilateral microphthalmia and coloboma, bilateral optic nerve hypoplasia, ventricular and atrial septal defects, and growth delays. We found two sequence variants in SALL4 - c.[575C>A], predicting p.(Ala192Glu), that was paternally inherited, and c.[2053G>C], predicting p.(Asp685His), that was maternally inherited. Haploinsufficiency for SALL4 due to nonsense or frameshift mutations has been associated with acro-renal ocular syndrome that is characterized by eye defects including Duane anomaly and coloboma, in addition to radial ray malformations and renal abnormalities. Our report is the first description of structural eye defects associated with two missense variants in SALL4 inherited in trans; the absence of reported findings in both parents suggests that both sequence variants are hypomorphic mutations and that both are needed for the ocular phenotype. SALL4 is expressed in the developing lens and regulates BMP4, leading us to speculate that altered BMP4 expression was responsible for the eye defects, but we could not demonstrate altered BMP4 expression in vitro after using small interfering RNAs (siRNAs) to reduce SALL4 expression. We conclude that SALL4 hypomorphic variants may influence eye development.

Kidney diseases are becoming a major cause of global burden with high mortality and morbidity. The origins of most kidney diseases are known, but for some the exact aetiology is not yet understood. Dermatoglyphics is the scientific study of epidermal ridge patterns and it has been used as a non-invasive diagnostic tool to detect or predict different medical conditions that have foetal origin. However, there have been a limited number of studies that have evaluated a dermatoglyphic relationship in different kidney diseases. The aim of this review was to systematically identify, review and appraise available literature that evaluated an association of different dermatoglyphic variables with kidney diseases. This review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. The PubMed(®) (Medline), POPLINE, Cochrane Library and Trip Database and grey literature sources such as OpenGrey, Google Scholar, and Google were searched to earliest date to 17 April 2014. Of the 36 relevant publications, 15 were included in the review. Of these studies, there are five case reports, seven case series and three comparative studies. Possible association of dermatoglyphics with Wilms tumor (WT) had been evaluated in two comparative studies and one case series that found fewer whorls and a lower mean total ridge count (TRC). Another study evaluated adult polycystic kidney disease (APCD) type III that revealed lower TRC means in all cases. All other case series and case reports describe dermatoglyphics in various kidney disease such as acro-renal-ocular syndrome, potter syndrome, kabuki makeup syndrome, neurofaciodigitorenal syndrome, syndactyly type V, ring chromosome 13 syndrome, trisomy 13 syndrome and sirenomelia. It is evident that whorl pattern frequency and TRC have been used widely to investigate the uncertainty related to the origin of several kidney diseases such as WT and APCD type III. However, small sample sizes, possibly methodological issues, and discrepancy in the make up between cases and control groups limits interpretation of any significant findings. Future studies with proper protocol, adequate cases, and control groups may provide stronger evidence to resolve uncertainty related to the aetiology of kidney diseases.