Patient 1 was noted to have decreased fetal movement, and he was delivered at term by cesarean because of breech presentation weighing 3430 g and measuring 51 cm in length. He was born with severe anal stenosis, which was repaired shortly after birth, followed by anal dilatation and repeat rectal surgery at age 5 years. He had generalized hypotonia, poor suck, feeding problems, tracheomalacia, congenital heart defects (ventricular septal defect with anomalous right ventricular muscle bundle, infundibular pulmonary stenosis, and right bundle branch block), relative macrocephaly, small ears, broad high forehead, flat nasal bridge, down-slanted palpebral fissures, ocular hypertelorism, ptosis (), broad thumbs and halluces, and sacral dimple. A maternal uncle of his mother died at age 6 years with a similar facial appearance, generalized hypotonia, anal and cardiac defects, and an outgoing personality with a quick temper. A second affected brother died shortly after birth. For this reason, an X-linked recessive disorder was suspected.
Patient 1 at ages 3 years, 5 years, 13 years and 15 years demonstrating characteristic facial features of relative macrocephaly, small ears, broad high forehead, flat nasal bridge, downslanted palpebral fissures, ocular hypertelorism, and ptosis.
He had chronic constipation and recurrent impaction treated with laxatives and manual disimpactions. As an adult, he developed rectal prolapse and hemorroids. Persistent respiratory infections required frequent hospitalizations due to tracheomalacia, and small ear canals had frequent wax obstruction. He had persistent hypotonia and drooling, and global developmental delay with better receptive language skills than expressive skills. A right optic and retinal coloboma was diagnosed at 18 months during an evaluation for alternating esotropia. His cardiac defects were treated initially with digoxin and then surgically repaired at age 3 years. Subluxing patellae resulted in repeated falls, treated initially with braces and finally by surgery at age 17.
He had moderate cognitive disability (full-scale IQ 49, verbal IQ 55, performance IQ 51) and required special education. Brain MRI showed agenesis of corpus callosum. He was diagnosed with attention deficit hyperactivity disorder (ADHD) in early childhood and with Tourette syndrome at age 10 years. He was easily frustrated and had extensive temper outbursts that lasted for hours until he exhausted himself. He manifested verbal and motor tics, was extremely impulsive, and had to be watched constantly for his own protection. He also developed unusual habits and rituals (e.g. licking his hands and rubbing saliva on his face, his stomach and the bottoms of his feet). He was treated with methylphenidate hydrochloride for ADHD, which did not stop his tics, impulsiveness or ritualistic behaviors at home, but teachers felt he was more attentive with fewer outbursts at school.
Methylphenidate hydrochloride was subsequently discontinued, and although he was still impulsive and hyperactive, he became calmer and happier. He had persistent problems with drooling and constipation, and at age 11 years, his behavior deteriorated, and he became extremely obsessive and compulsive, with almost constant verbal and motor tics and severe temper outbursts. He was treated with haloperidol, which reduced his tics and resulted in calmer behavior until early adolescence, but he remained extremely impulsive. When he reached maximal doses of haloperidol, fluoxetine hydrochloride was added, but his behaviors worsened, and he became suicidal and obsessed with knives, requiring an inpatient psychiatric admission to wean him off all medications.
He was placed in various group home settings, where he was closely supervised over the next few years, meeting regularly with his team of teachers, group home staff and specialists in behavior management. Success was attributed to consistency, understanding, and mutual trust between the patient and his care-providers. At age 16, shortly after the death of his father, he had a serious incident when he threatened the staff at his group home with a knife, resulting in his discharge and admission to an adult psychiatric ward for three weeks. He returned home to live with his mother. As he became more able to self-monitor his behaviors and learned some coping skills through counseling, his temper outburst became less frequent. His most difficult issues were with obsessive compulsive disorder (OCD), which was treated with pimozide. Propranolol was also prescribed for a time, but he began to gain weight and to eat obsessively, so this was discontinued.
He graduated from high school at age 20, and went on to work with Good Will Industries, where he began the transition from school to work in a supported living environment in one side of a duplex he shared with his mother. Even though he continued to have seasonal challenging and difficult behaviors with temper outbursts, they became less frequent, and he seemed to thrive and mature in this new setting. He had difficulty with uncontrollable drooling his entire life, and at age 20 he began taking benztropene, which was effective in controlling his constant drooling. His tics resolved, but he continued to manifest OCD and remained on pimozide. He was generally self-controlled with use of medications and a one-on-one staffing program that met his needs through a very strict daily routine.
He was diagnosed with FG syndrome by Dr. James Hanson of the University of Iowa at age 16, and Dr. John M. Opitz confirmed this diagnosis at age 22, when he was 164 cm tall (3rd–5th centile), weighed 81 kg (75th centile), and had a head circumference (OFC) of 63 cm (>97th centile). As an adult, his most difficult issue continued to be OCD, so paroxetine hydrochloride was added to his treatment with pimozide. Within a few weeks of starting paroxetine hydrochloride, he lost the ability to control his behavior and developed more tics, so paroxetine hydrochloride was increased. He was weaned off pimozide, which was replaced with risperidone, but he reverted back to his previous behavioral problems while he was on haloperidol and fluoxetine hydrochloride. His tics became constant, so paroxetine hydrochloride was discontinued and risperidone was increased, which resulted in an excellent behavioral response. He tolerated a move to a new city, where he was able to make friends and participate in community programs. He has continued to prosper under the guidance of a psychologist at age 32, and he remains on risperidone as a mood stabilizer.
Patient 2 was born at term weighing 3289 g, measuring 51 cm in length with OFC of 34 cm. Apgar scores were 4 and 8. After birth, he was intubated and a tracheal plug was removed. He was initially diagnosed with severe anal stenosis, which was corrected with dilatation and anoplasty. As a neonate, he required surgery for pyloric stenosis. His heart was dextropositioned with a patent ductus arteriosus, ventricular septal defect, and atrial septal defect, which all resolved spontaneously. His thumbs were broad with duplication of the metacarpal and the proximal phalanx on the left side, and radiographs documented 13 ribs on the right side with a vertebral segmentation abnormality at T9 and T10. He had a high, broad forehead, large head size, upsweep of the frontal hair; high, narrow palate, and absent tear ducts, which required surgical correction at age 3 years.
During infancy, he developed seizures, beginning as absence or petit mal seizures, with development of grand mal seizures around age 2 years. These occurred primarily during sleep, with EEG abnormalities recorded on multiple occasions. An MRI showed cavum septi pellucidi and cavum vergae with a hypoplastic corpus callosum, dilated lateral and fourth ventricles, and mild cerebellar vermis hypoplasia. At times he had periodic absence episodes, and his seizures appeared to resolve in later childhood. Throughout his life, he has had persistent sleep abnormalities consisting of not sleeping through the night and getting up during the night. Exotropia was repaired at age 6 years.
He manifested global developmental delay and IQ testing documented a full-scale IQ of 49, with performance IQ 53 and verbal IQ 54, suggesting moderate cognitive disability at age 19 years, with communication skills at an age equivalent of 3 years 10 months, daily living skills at age equivalent 3–10, community and domestic skills at age equivalent 4–1, socialization skills at age equivalent 7–11, and interpersonal relationship skills at age equivalent 6–8. It was felt that some of his limitations in daily living skills were due to having been placed in a structured residential school setting at age 12 years, where many daily living tasks were completed by staff. He had mild sensorineural hearing loss bilaterally, which did not require hearing aids, and his hearing was adequate for daily functioning. He has had a life-long problem with chronic constipation, requiring manual disimpaction and laxatives.
His frequent urination has been attributed to a possible side effect of lithium. As a teen-ager he had a major psychiatric episode during which time he had excessive tantrums or manic behavior with aggression. He was hospitalized, and quite a number of medications were tried to help control his manic behavior at that time. Behavioral measures documented poor self-esteem and excessive anxiety, impulsivity and depression, especially during times of stress. Currently he is on citalopram, desmopressin, valproate, lithium, and lorazepam. These medications seem to have provided distinct improvement in his mood.
His adult height is at the 10th–25th centile with head circumference at the 90th centile. His ears are small (less than 3rd centile) with deficient lower helices, a frontal upsweep, a tall, narrow frontal forehead, fullness in the malar areas and prognathism (). He manifests a constant tongue-thrust with speech, persistent drooling, high palate and external strabismus of the left eye. He has pectus excavatum with broad, flat thumbs, particularly distally, and the nails tend to adhere distally to the soft tissues of the thumbs. The great toes are wide, and the nails are flat and adhere distally. Neurologically, his muscle tone in the limbs appears good, but he has some contracture at the elbows with out-toeing on ambulation. Reflexes are normal (2+ in the lower limbs and 1+ in the upper limbs). The diagnosis of FG syndrome was made by Dr. Elaine Zackai of Children’s Hospital of Philadelphia at age 7 and confirmed by Dr. John M. Opitz at age 15.
Patient 2 at age 24 years demonstrating relative macrocephaly (90th centile) with small ears (<3rd centile), tall narrow forehead, down-slanted palpebral fissures, ocular hypertelorism, ptosis, and broad flat thumbs and halluces.