CLINICAL REPORT
Cranioectodermal Dysplasia: A Probable Ciliopathy Anastasia E. Konstantinidou,1* Helen Fryssira,2 Stavros Sifakis,3 Charalampos Karadimas,4 Petros Kaminopetros,5 Georgios Agrogiannis,1 Stylianos Velonis,1 Peter G.J. Nikkels,6 and Efstratios Patsouris1 1
Department of Pathology, National Kapodistrian University Medical School, Athens, Greece Department of Medical Genetics, National Kapodistrian University Medical School, ‘‘Aghia Sophia’’ Children’s Hospital, Athens, Greece
2 3
Department of Obstetrics and Gynecology, University Hospital of Heraklion, Crete, Greece
4
Department of Genetics, Institute of Child Health, Aghia Sophia Children’s Hospital, Athens, Greece The Fetal Medical Practice, Athens, Greece
5 6
Department of Pathology, University Medical Center, Utrecht, The Netherlands
Received 17 February 2009; Accepted 15 June 2009
Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is a rare autosomal recessive genetic disorder characterized by typical craniofacial, skeletal and ectodermal defects, and tubulointerstitial nephritis leading to early end-stage renal failure. We report on a new familial case of a 9-year-old patient and two fetuses of 23 and 19 weeks of gestation respectively. Hypohidrosis was an additional ectodermal finding is the patient with CED. Postmortem findings in the two fetuses included acromesomelic shortening, craniofacial characteristics with absence of craniosynostosis, small kidneys with tubular and glomerular microscopic cysts, persistent ductal plate with portal fibrosis in the liver, small adrenals and roughly unremarkable histopathology of the physeal growth plate. Posterior fossa anomalies were additional findings in this patient and included an enlarged cisterna magna and a posterior fossa cyst. The above findings, in association with renal cysts, persistent ductal plate and portal fibrosis, introduce CED, a nonlethal genetic skeletal disorder of yet unknown molecular origin, as a possible member of the expanding group of ciliopathies. 2009 Wiley-Liss, Inc.
Key words: cranioectodermal dysplasia; Sensenbrenner syndrome; fetus; postmortem; renal cysts; persistent ductal plate; ciliopathy; hepatorenal fibrocystic syndrome; posterior fossa
INTRODUCTION Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome (OMIM #218330) is a rare autosomal recessive skeletal dysplasia characterized by defects of ectoderm-derived structures associated with short limbs, brachydactyly, narrow thorax, dolichocephaly with frontal bossing and craniosynostosis [Levin et al., 1977; OMIM, 2006]. Progressive renal failure, heart defects, recurrent respiratory infections and ocular disorders are the main extraskeletal features of the syndrome [OMIM, 2006]. Herein we report on a familial CED case of a 9-year-old girl and two consecutive affected female fetuses of 23 and 19 weeks of gestational age respectively. This is the first report to describe the detailed
2009 Wiley-Liss, Inc.
How to Cite this Article: Konstantinidou AE, Fryssira H, Sifakis S, Karadimas C, Kaminopetros P, Agrogiannis G, Velonis S, Nikkels PGJ, Patsouris E. 2009. Cranioectodermal dysplasia: A probable ciliopathy. Am J Med Genet Part A 149A:2206–2211.
postmortem, radiographic, and histopathologic findings in fetuses affected with CED.
CLINICAL REPORT AND METHODS Patient 1 The 9-year-old proposita was the second child of Caucasian parents originating from the same small village of Crete, Greece, with no known consanguinity. The mother, G7P2 in total, had three previous first trimester spontaneous abortions, a normal girl and two subsequently affected pregnancies. The proposita was born at 38 weeks of gestation complicated by intrauterine growth restriction and oligohydramnios. Dysmorphic craniofacial features were present from birth, and included dolichocephaly, ptosis of the eyes, epicanthal folds, retrognathia, high arched palate, anteverted lower lip with protruding tongue and low set ears with abnormal helices. Growth parameters were low, with height, weight, and head circumference below the 3rd centile. Brachymelia, brachydactyly with skin syndactyly, abnormal dermatoglyphic pattern and short broad nails were noticed *Correspondence to: Anastasia E. Konstantinidou, M.D., Ph.D., 75, M.Asias str. 11527 Athens, Greece. E-mail:
[email protected] Published online 16 September 2009 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.a.33013
2206
KONSTANTINIDOU ET AL. (Fig. 1A). Later, small, widely spaced teeth and fine sparse hair were evident. Teeth erupted with delay at about 15 months of age. Ultrasonographic evaluation soon after birth showed small hyperechogenic kidneys and impairment of renal function was detected at 7 days of life with urea at 1.0 mg/dl and creatinine at 1.3 mg/dl. A radiologic examination revealed craniosynostosis of the sagittal and right coronal sutures, narrow thorax with mildly dysplastic ribs and short acromesomelic tubular bones (Fig. 1B). In addition, the first
2207 metacarpals were wide and there was a triphalangeal hallux. The findings of acromesomelic skeletal dysplasia with craniosynostosis, associated with ectodermal disorders, were typical of CED. Additional extraskeletal findings included a mild mitral insufficiency and a large cisterna magna on the brain MRI (Fig. 2A) (not previously described in patients with CED). Infancy and early childhood were remarkable for chronic renal failure associated with diabetes insipidus and recurrent respiratory infections with
FIG. 1. A, Left: The proposita at 3 years of age. Right: Brachydactyly and webbing of middle toes. B: Radiography at 2 years of age. Left: Narrow thorax with horizontal ribs. Middle: Short tubular bones of the upper limb with bowed humerus and abnormal upper epiphysis; short metacarpal and phalangeal bones with short broad first metacarpals. Right: Short tibia and fibula with flared metaphyses. C: The proposita at 9 years of age. D: The 19-week fetus shows some morphogenetic features of CED (microretrognathia, large anteverted lower lip, protruding tongue, low-set ears). E: Radiography of the 23-week fetus. There is upper mesomelic bowing (radius and ulna), lower mesomelic shortening and bowing (tibia and fibula), and relatively short, abnormal ribs. Fresh fractures of the humeri are most likely traumatic. F: Babygrams of the 19-week fetus show similar findings to E. Flared metaphyses are evident.
2208
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 2. Posterior fossa anomalies in Patients 1 and 2. A: Brain MRI of Patient 1 depicting enlarged cisterna magna. B: Prenatal ultrasonographic scan of Patient 2 at 20þ3 weeks of gestation shows a posterior fossa cyst.
dyspnea, which became less frequent with time. At 4 years of age she reached end-stage renal failure and was commenced on peritoneal dialysis. Transient hepatomegaly was noted during an episode of peritonitis, without any signs of progressive liver dysfunction. An attempt of renal transplantation resulted in hyperacute rejection of the cadaveric transplant. At 9 years of age she was in relatively good health, expecting a second attempt of renal transplantation. She weighed 18 kg and measured 102 cm (
