MedGen

Auriculocondylar syndrome-1 (ARCND1) is an autosomal dominant disorder of the first and second pharyngeal arches and is characterized by malformed ears (question mark ears), prominent cheeks, microstomia, abnormal temporomandibular joint, and mandibular condyle hypoplasia (summary by Masotti et al., 2008). Genetic Heterogeneity of Auriculocondylar Syndrome See also ARCND2A (614669) and ARCND2B (620458), caused by heterozygous or biallelic mutation, respectively, in the PLCB4 gene (600810) on chromosome 20p12; ARCND3 (615706), caused by mutation in the EDN1 gene (131240) on chromosome 6p24; and ARCND4 (620457), caused by mutation the HDAC9 gene (606543) on chromosome 7p21. See also 612798 for isolated question mark ears. Reviews Kokitsu-Nakata et al. (2012) tabulated clinical findings in 24 reported cases of auriculocondylar syndrome. The most common clinical signs observed were ear constriction (100%), abnormal temporomandibular joint (100%), mandibular condyle abnormality (93%), malocclusion (93%), round face (78%), microstomia (78%), micrognathia (78%), prominent cheeks (74%), hearing loss (56%), abnormal palate (55%), and crowded teeth (50%). The authors noted that the phenotype was highly variable in severity, even within families. Liu et al. (2021) reviewed 19 published cases of ARCND1 and tabulated the common features, including micrognathia (79%), auricular malformation (68%), microstomia (67%), prominent cheeks (63%), mandibular hypoplasia (58%), and round face (58%). Asymmetry of mandibular and auricular malformations was present in 4 patients, and the lesions were either more severe on the right or only the right side was affected, suggesting a predilection for right-sided deformities. The authors also noted that severe cases mostly occurred in female patients. Prenatal findings were available in 3 patients, and all showed polyhydramnios, with 2 having micrognathia evident on ultrasonography. The authors suggested that severe micrognathia and mandibular hypoplasia accompanied by polyhydramnios might be prenatal indicators of ARCND. Using a standardized questionnaire sent to referring physicians, Vegas et al. (2022) collected clinical data on 39 patients from 27 families with auriculocondylar syndrome and mutation in the GNAI3, PLCB4, or EDN1 genes. PLCB4 was the most common gene associated with ARCND, being mutated in 16 (59%) of the 27 families. Incomplete penetrance and/or variable expression was observed within families. [from OMIM]

TRNT1 deficiency encompasses what was first thought to be two separate disorders, a severe disorder called sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) and a milder disorder called retinitis pigmentosa with erythrocytic microcytosis (RPEM), each named for its most common features. SIFD begins in infancy, and affected individuals usually do not survive past childhood. RPEM, on the other hand, is recognized in early adulthood, and the microcytosis usually does not cause any health problems. However, it has since been recognized that some individuals have a combination of features that fall between these two ends of the severity spectrum. All of these cases are now considered part of TRNT1 deficiency.

In addition, many individuals with TRNT1 deficiency have recurrent fevers that are not caused by an infection. These fever episodes are often one of the earliest recognized symptoms of TRNT1 deficiency, usually beginning in infancy. The fever episodes are typically accompanied by poor feeding, vomiting, and diarrhea, and can lead to hospitalization. In many affected individuals, the episodes occur regularly, arising approximately every 2 to 4 weeks and lasting 5 to 7 days, although the frequency can decrease with age.

Many people with TRNT1 deficiency have an immune system disorder (immunodeficiency) that can lead to recurrent bacterial infections. Repeated infections can cause life-threatening damage to internal organs. The immunodeficiency is characterized by low numbers of immune system cells called B cells, which normally help fight infections by producing immune proteins called antibodies (or immunoglobulins). These proteins target foreign invaders such as bacteria and viruses and mark them for destruction. In many individuals with TRNT1 deficiency, the amount of immunoglobulins is also low (hypogammaglobulinemia).

A common feature of TRNT1 deficiency is a blood condition called sideroblastic anemia, which is characterized by a shortage of red blood cells (anemia). In TRNT1 deficiency, the red blood cells that are present are unusually small (erythrocytic microcytosis). In addition, developing red blood cells in the bone marrow (erythroblasts) can have an abnormal buildup of iron that appears as a ring of blue staining in the cell after treatment in the lab with certain dyes. These abnormal cells are called ring sideroblasts.

Neurological problems are also frequent in TRNT1 deficiency. Many affected individuals have delayed development of speech and motor skills, such as sitting, standing, and walking, and some have low muscle tone (hypotonia).

Eye abnormalities, often involving the light-sensing tissue at the back of the eye (the retina), can occur in people with TRNT1 deficiency. Some of these individuals have a condition called retinitis pigmentosa, in which the light-sensing cells of the retina gradually deteriorate. Eye problems in TRNT1 deficiency can lead to vision loss.

Features that occur less commonly in people with TRNT1 deficiency include hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss), recurrent seizures (epilepsy), and problems with the kidneys or heart.

TRNT1 deficiency is a condition that affects many body systems. Its signs and symptoms can involve blood cells, the immune system, the eyes, and the nervous system. The severity of the signs and symptoms vary widely. [from MedlinePlus Genetics]