How to Cite this Article: Caglayan AO, Stevens SJC, Albrechts JCM, Dundar M, Engelen J. 2012. A new syndrome of microtia with unilateral renal agenesis and short stature. Am J Med Genet Part A. 158A:1837–1840.
In the general population, unilateral renal agenesis occurs in about 0.3 per 682 [Roodhooft et al., 1984]. The incidence of anotia/microtia is relatively rare—occurring in approximately 1.46–17.4 per 10,000 live births in different populations [Castilla and Orioli, 1986; Mastroiacovo et al., 1995; Wang et al., 2001]. Previous studies have proposed that a child with external ear malformations have a greater risk of structural renal anomalies compared with the general population [Wang et al., 2001]. In addition prior studies found that in children with ear anomalies, defects within other organ systems occur with a frequency of 5–40% [Mastroiacovo et al., 1995; Harris et al., 1996; Wang et al., 2001]. Ear and renal anomalies are components of many multiple congenital anomaly syndromes including CHARGE syndrome, Townes–Brocks syndrome, and Goldenhar syndrome. Here, we describe a distinct case with microtia, short stature, external ear abnormality, and unilateral renal agenesis, who we posit has a previously unidentified syndrome.
A 13-month-old girl with multiple malformations was admitted to our clinic for assessment of short stature. She was born at 38 weeks gestation by cesarean due to breech presentation at a local hospital. She was the first child of a 24-year-old woman married to her 27-year-old first cousin. The mother had not attended prenatal care clinics during the pregnancy. She did not report diabetes, any infection, or exposure history to drugs or teratogens. Parents did not report any history of congenital abnormalities in the family. At birth growth parameters of the patient were below the 3rd centile. In her postnatal history, there was no feeding difficulties and hypertonicity in the newborn period.
On physical examination, she had growth retardation. Her weight was 5.2 kg (<3rd centile), height was 62 cm (<3rd centile), and head circumference was 40 cm (<3rd centile). Bitemporal narrowing of the head, microtia severity type 2 (cupped abnormality of superior underdeveloped helix, antihelix, uplifted ear lobe), long philtrum, micrognathia, bilateral single transverse crease, and skin syndactyly between second and third toes were noted. In addition, she had no ear or branchial tags or pits, and no synophrys, arched eyebrows, micromelia, or hirsutism (Fig. 1).
At that time serum and urine amino acids, serum lactate and pyruvate, creatine kinase, ammonia, blood chemical parameters, and complete blood count parameters were normal. Her whole abdominal ultrasonography showed agenesis of the left kidney and a small right kidney (3.5 cm × 1.5 cm). Results of echocardiography, auditory brain response (ABR) temporal bone computed tomography, magnetic resonance imaging of inner ear, and brain MRI were normal. The GTG banded karyotype from peripheral blood cells was 46,XX in all 30 cells analyzed. Ophthamologic examination was normal.
To investigate whether chromosomal gains or losses were underlying the clinical phenotype, copy number variation (CNV) profiling of whole-blood DNA of the girl and both parents was performed using the GeneChip® Human Mapping 250 K NspI. DNA samples of 40 healthy females were used as the reference population. Karyotypes were designated according to ISCN 2009 [Shaffer et al., 2009]. This did not show any aberrations and the karyotype of the girl was designated as arr(1–22,X)x2. However, high homozygosity (∼30 regions) with CNV were found, which were not seen in the reference samples. This could be explained by the fact that the parents were consanguineous. Using a literature mining tool that links phenotype information to genomic aberrations at the chromosome band level [Van Vooren et al., 2007], we found no leads for further candidate gene screening in the absence of heterozygosity (LOH) regions.
Microtia is a congenital malformation of the auricle, ranging from a measurably small external ear with minimal structural abnormality, to an ear with major structural alteration including anotia; the total absence of the pinna [Hunter et al., 2009]. Microtia can occur either as an isolated defect or in association with other defects. It can be unilateral or bilateral, and the severity of microtia is not different in unilateral and bilateral cases [Carey, 1993; Harris et al., 1996]. Microtia has been reported to occur predominantly in males. Only in a minority of cases has monogenic forms with autosomal dominant or recessive inheritance of microtia without known syndromes have been described (OMIM #600674). Environmental causes for microtia have been found and include maternal climostes and isotretion [Swartz and Faerber, 1985; Adam et al., 2003; Tischfield et al., 2005; Tekin et al., 2007; Alasti et al., 2008].
Ear and kidney abnormalities occurring together were first reported by Potter . Population studies do show an increased incidence of renal malformations in children with ear anomalies [Roodhooft et al., 1984]; however, no set of uniform standards exists in determining which types of ear anomalies require renal imaging. Wang et al.  suggest that a patient with isolated preauricular pit(s), cup ears, or an ear anomaly accompanied by positive findings in any of these areas should undergo a renal sonogram to assist in the diagnosis of these syndromes. Otherwise, a renal ultrasound is not recommended [Wang et al., 2001].
Microtia occurs when the tissues that form the auricle fail to develop properly. Embryologically, ear and kidney primordia arise at different times and develop at different rates. Therefore, the association between ear and kidney anomalies is not usually due to an isolated insult to the embryo that affects both developing structures at the same time. In most cases of microtia with renal defects the combination is usually part of a specific pattern of multiple congenital anomalies, particularly CHARGE syndrome (OMIM #214800), Goldenhar syndrome (OMIM #164210), Townes–Brocks syndrome (OMIM #107408), branchio-oto-renal syndrome (OMIM #113650), Nager syndrome (OMIM #154400), Treacher Collins syndrome (OMIM #154500), various teratogenic embryopathies or chromosomal syndromes (trisomies of 13, 18, 21, 22, and deletions of a chromosome arm 5p, 18p, and 18q) [Harris et al., 1996; Ishimoto et al., 2005]. Among infants with microtia, bilateral defects were more frequent in those with a genetic syndrome the patient described herein. We report on a female with multiple congenital anomalies, including proportionate short stature, microtia, multiple minor anomalies, and agenesis of the left kidney and a small right kidney. None of the above-mentioned syndromes fit our patient, although several features are shared with some (Table I).
Table I. Comparison of Case' Clinical Findings With Other Similar Syndromes
Patients with auricular anomalies should be assessed carefully for accompanying dysmorphic features and other findings, including holoprosencephaly, facial asymmetry; anophthalmia or microphthalmia, colobomas of the lid, iris, and retina; hearing loss, choanal atresia; cleft lip or palate, micrognathia, branchial cysts or sinuses; cardiac malformation; limb defects, vertebral anomalies, and imperforate or anteriorly placed anus. If any of these features are present, then a renal ultrasound is beneficial, not only in discovering renal anomalies but also in the diagnosis and management of MCA syndromes [Izzedine et al., 2004].
The incidence of inner ear abnormalities associated with microtia is estimated between 10% and 47% [Stoll et al., 1997]. Wang et al.  noted that a significant percentage of children with ear anomalies have some degree of hearing loss, and early detection and referral to an ear, nose, and throat specialist for management are often necessary [Wang et al., 2001].
Recently, Demir et al.  described a male with multiple congenital anomalies including microtia and unilateral renal agenesis. However, the absence of other features seen in this syndrome including preauricular skin tag with conductive hearing loss, partial syndactyly of the fourth and fifth metacarpals, multiple tarsal coalitions, absent toe, and hypoplastic tibia and fibula in the patient reported have excludes this syndrome.
We have searched the genetic literature and databases, such as OMIM, POSSUM, and London dysmorphology medical database (LDDB) and we could not match any with the present. Given the history of the parent consanguinity, we conclude that the phenotypic findings described in this patient probably represent an autosomal recessively keys and novel MCA syndrome. Nowadays, exome sequencing performed successfully to discover the gene for a rare Mendelian disorder of unknown cause, and the identification of such genes could reveal novel information on craniofacial development.