Cochat et al. (1988) described the association of diffuse leiomyomatosis with Alport syndrome in 12 patients from 5 pedigrees. All the patients had at least hematuria and esophageal leiomyomatosis. Seven of 9 examined had cataracts, 4 of 6 ... Cochat et al. (1988) described the association of diffuse leiomyomatosis with Alport syndrome in 12 patients from 5 pedigrees. All the patients had at least hematuria and esophageal leiomyomatosis. Seven of 9 examined had cataracts, 4 of 6 had deafness, and 5 of 6 females also had genital leiomyomatosis. Tracheobronchial leiomyomatosis was discovered at autopsy in 3. The symptoms of esophageal involvement appeared as early as the age of 30 months. The tumors in the esophagus were always multiple and occasionally extended into the stomach. Sporadic cases of this syndrome were reported by Blank and Michael (1963), Johnston et al. (1953), and Kenny (1953). (See 150700 for a syndrome of leiomyoma of vulva and esophagus; this combination should prompt search for other features of Alport syndrome in the female patient herself or in male relatives.) DL-ATS may have been present in the Mexican-Indian boy, aged 7 years 9 months, reported by Leichter et al. (1988). The boy had a 3-year history of wheezing, coughing, dyspnea, and postprandial vomiting of undigested food, as well as failure to thrive. He was found to have hematuria, proteinuria, and decreased renal function. Electron microscopy of a renal biopsy specimen showed glomerular basement membrane changes typical of Alport syndrome. Audiometry showed moderate bilateral high-tone sensorineural hearing loss; bilateral anterior lenticonus and unilateral cataract were found on ophthalmologic examination. Legius et al. (1990) described a patient with sporadic occurrence, who had diffuse muscular hypertrophy of the esophagus, bilateral cataracts, and an Alport-like nephropathy, but concluded that the glomerular lesions in this disorder differed from those in Alport syndrome in several respects. Renieri et al. (1994) and Segal et al. (1999) reported an adopted 30-year-old man diagnosed with Alport syndrome at 6 years of age. He progressed to end-stage renal disease by age 16 years and subsequently underwent renal transplantation. Esophageal leiomyomas were diagnosed during his early twenties. He had bilateral high-tone hearing loss and bilateral cataracts with right lenticonus. Segal et al. (1999) also reported a 29-year-old man in whom hematuria was first detected at the age of 11 years. Typical histologic changes of ATS were found on renal biopsy at age 16 years. Progression to end-stage renal disease occurred by age 25 years. Esophageal leiomyomas were partially resected at age 17 years. Bilateral cataracts and sensorineural hearing loss were documented during the patient's twenties. His sister progressed to end-stage renal disease by age 30 years. She underwent partial resection of esophageal leiomyomas and resection and reconstructive surgery for vulvar leiomyomas during her teens. During her twenties, she underwent anal sphincterotomy and excision of the internal anal sphincter, for severe constipation secondary to hypertrophy of these structures. She had bilateral cataracts and asthma. The mother of these 2 patients, aged 60 years, underwent esophagomyotomy at age 40 years. She had microscopic hematuria and a serum creatinine level of 1.3 mg/dl. She had no clinically evident hearing loss or ocular abnormalities. Anker et al. (2003) described a 9-year-old boy with newly diagnosed sensorineural deafness. He was born with cataracts and presented symptoms of dysphagia and bronchial irritation in the first year of life. Macroscopic hematuria was first noticed at 2 years of age during a febrile infection. Since early childhood the boy suffered from severe constipation. Because of the manifestations, the diagnosis of Alport syndrome with diffuse leiomyomatosis was considered. Genetic analysis demonstrated the predicted deletion of the COL4A5/COL4A6 genes.
Heidet et al. (1995) developed a long-range restriction map around the COL4A6 locus and showed that the COL4A5/COL4A6 deletion observed in 7 patients with the diffuse leiomyomatosis/Alport syndrome complex encompassed only the first 2 exons of COL4A6, with ... Heidet et al. (1995) developed a long-range restriction map around the COL4A6 locus and showed that the COL4A5/COL4A6 deletion observed in 7 patients with the diffuse leiomyomatosis/Alport syndrome complex encompassed only the first 2 exons of COL4A6, with a breakpoint located in the second intron of COL4A6, whose size exceeds 65 kb. They also found that 3 patients with Alport syndrome without leiomyomatosis who had a deletion of the 5-prime part of the COL4A5 gene displayed a larger deletion in COL4A6. Moreover, a COL4A6 mRNA product was detected by RT-PCR in an esophageal tumor sample of a patient with DL-ATS. These results suggest that DL-ATS is caused by an abnormal truncated alpha-6(IV) chain. The COL4A6 breakpoint of the contiguous gene deletions of the COL4A5 and COL4A6 genes is invariably located in the large intron 2 of COL4A6. Heidet et al. (1997) described 4 YAC clones covering the locus and a refined restriction map of the entire COL4A6 gene. Using these resources, they determined the size of the COL4A6 gene to be approximately 350 kb. This result confirmed that COL4A6 was the largest type IV collagen gene known to date, although this estimated size was smaller than that made by Srivastava et al. (1995) from a megabase YAC contig. A striking feature of the gene's structure is the 275-kb length of introns 2 and 3, constituting almost three-fourths the entire length of the gene. The description of deletions in 5 additional unrelated patients reinforced the hypothesis that patients with deletions extending farther than exon 3 in COL4A6 do not develop muscle tumors, whereas patients who do have tumors possess COL4A6 breakpoints in intron 2.